Tricyclic N-heteroaryl-carboxamide derivatives containing a benzimidazole unit, method for preparing same and their therapeutic use

ABSTRACT

The invention concerns tricyclic N-heteroarylcarboxamide derivatives containing a benzimidazole unit of general formula (I): 
                         
Wherein A, P, Y, R 1 , R 2  and R 3  are as defined herein. The invention also concerns a method of preparing the compounds and their therapeutic use.

This application is a continuation of International application No. PCT/FR2007/000,183, filed Feb. 1, 2007, which is incorporated herein by reference in its entirety; which claims the benefit of priority of French Patent Application No. 06/01,007, filed Feb. 3, 2006.

The invention relates to tricyclic N-heteroarylcarboxamide derivatives containing a benzimidazole unit, to the preparation thereof and to the therapeutic use thereof.

A subject of the invention is compounds derived from tricyclic N-heteroarylcarboxamides containing a benzimidazole unit, which have an antagonist or agonist activity in vitro and in vivo with respect to TRPV1 (or VR1) type receptors.

A subject of the invention is the compounds corresponding to formula (I)

in which:

A is, with the C—N bond of the benzimidazole unit with which it is fused, a 4- to 7-membered monocyclic heterocycle or monocyclic heteroaryl, containing from one to three heteroatoms selected from O, S and N, including the nitrogen atom of the benzimidazole unit;

P is an 8-, 9-, 10- or 11-membered bicyclic hetero-cycle or bicyclic heteroaryl, comprising from 1 to 6 heteroatoms selected from N, O and S; P being linked to the —C(Y)— group by a carbon atom;

-   -   with the proviso that, when A is a 7-membered saturated         heterocycle, P is other than the 2,3-dihydro-1,4-benzodioxane         group, the 1-benzopyran-2-one group and the isoindole group;

R₁ is from one to four atoms or groups, which may be identical or different, selected from a hydrogen atom, a halogen atom, and an oxo, thio, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, aryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl, heteroaryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, hetero-arylthio-C₁-C₆-alkyl, aryl-C₁-C₃-alkylenethio-C₁-C₆-alkyl, heteroaryl-C₁-C₃-alkylenethio-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy, C₁-C₆-fluoroalkoxy, cyano, C(O)NR₄R₅, nitro, NR₄R₅, C₁-C₆-thioalkyl, C₃-C₇-cycloalkylthio, C₃-C₇-cycloalkyl-C₁-C₃-alkylenethio, —S(O)—C₁-C₆-alkyl, —S(O)—C₃-C₇-cycloalkyl, —S(O)—C₁-C₃-alkylene-C₃-C₇-cycloalkyl, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, SO₂NR₄R₅, SF₅, NR₆C(O)R₇, NR₆SO₂R₈, R₄R₅NC(O)—C₁-C₃-alkylene, aryl, heteroaryl, aryl-C₁-C₅-alkylene, heteroaryl-C₁-C₅-alkylene, aryloxy, arylthio, heteroaryloxy or heteroarylthio group;

said heteroaryl or aryl groups of R₁ being optionally substituted with one or more substituents R₉, which may be identical to or different from one another;

with the proviso that, when R₁ is attached to a nitrogen atom of P, then R₁ is different from a halogen atom, and from an oxo, thio, cyano, nitro, SF₅, NR₄R₅, C₁-C₆-thioalkyl, thioaryl, thioheteroaryl, C₁-C₆-alkoxy, aryloxy, heteroaryloxy, —NR₆COR₇ and NR₆SO₂R₈ group;

Y is an oxygen or sulphur atom;

R₂ is a hydrogen atom, a halogen atom, or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl or C₁-C₆-alkoxy group;

R₃ is from one to three atoms or groups, which may be identical or different, selected from a hydrogen atom, a halogen atom, and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, hydroxyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy or C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy group, when R₃ is carried by a carbon atom;

or

R₃ is from one to two atoms or groups, which may be identical or different, selected from a hydrogen atom, a halogen atom, and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C(O)—, C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-C(O)—, C₁-C₆-fluoroalkyl-C(O)—, aryl-S(O)₂—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, C₁-C₆-alkyl-O—C(O)—, aryl-C₁-C₃-alkyl-O—C(O)—, C₃-C₇-cycloalkyl-O—C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-O—C(O)—, C₁-C₆-fluoroalkyl-O—C(O)—, aryl-O—C(O)— or heteroaryl-O—C(O)— group, when R₃ is carried by a nitrogen atom;

R₄ and R₅ are, independently of one another, a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₅-alkylene or aryl group;

or R₄ and R₅ form, together with the nitrogen atom which carries them, an azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, the NR₄R₅ group being optionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene, aryl, heteroaryl, aryl-S(O)₂—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cyclo-alkyl-C₁-C₃-alkylene-S(O)₂—, aryl-C(O)—, C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-C(O)—, C₁-C₆-fluoroalkyl-C(O)—, hydroxyl, C₁-C₆-alkyloxy, C₁-C₆-fluoroalkyl, aryloxy-C₁-C₆-alkylene, aryloxy, heteroaryloxy-C₁-C₆-alkylene or heteroaryloxy group;

R₆ and R₇ are, independently of one another, a hydrogen atom, or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene or aryl group;

or R₆ and R₇ together form a 4- to 7-membered lactam comprising the nitrogen atom and the C(O) group which carry them;

R₈ is a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene or aryl group;

or R₆ and R₈ together form a 4- to 7-membered sultam comprising the nitrogen atom and the S(O)₂ group which carry them;

R₉ is a halogen atom, or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkoxy, nitro, cyano, NR₄R₅, R₄R₅N—C₁-C₃-alkylene, aryl, heteroaryl, aryloxy, arylthio, heteroaryloxy or heteroarylthio group, said heteroaryl or aryl groups being optionally substituted with one or more substituents selected from a halogen atom, and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkoxy, nitro, cyano, NR₄R₅ or R₄R₅N—C₁-C₃-alkylene group.

In the compounds of formula (I):

-   -   the sulphur atom(s) of the heterocycle A may be in oxidized form         (S(O) or S(O)₂);     -   the nitrogen atom(s) may be in oxidized form (N-oxide).

The compounds of formula (I) may contain one or more asymmetrical carbon atoms. They may therefore exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, are part of the invention.

The compounds of formula (I) may exist in the form of bases or of addition salts with acids. Such addition salts are part of the invention.

These salts may be prepared with pharmaceutically acceptable acids, but the salts of other acids that can be used, for example, for purifying or isolating the compounds of formula (I) are also part of the invention.

The compounds of formula (I) may also exist in the form of hydrates or of solvates, i.e. in the form of associations or of combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.

In the context of the present invention, the term:

-   -   “a halogen atom” is intended to mean: a fluorine, a chlorine, a         bromine or an iodine;     -   “C_(t)-C_(z)” is intended to mean: a carbon-based chain that may         have from t to z carbon atoms where t and z can have the values         from 1 to 7; for example, C₁-C₃ is a carbon-based chain which         may have from 1 to 3 carbon atoms;     -   “an alkyl” is intended to mean: a linear or branched, saturated         aliphatic group. By way of examples, mention may be made of         methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,         pentyl, etc., groups;     -   “an alkylene” is intended to mean: a linear or branched,         saturated divalent alkyl group, for example a C₁₋₃-alkylene         group is a linear or branched, divalent carbon-based chain         having from 1 to 3 carbon atoms, more particularly a methylene,         ethylene, 1-methylethylene or propylene;     -   “a cycloalkyl” is intended to mean: a cyclic alkyl group. By way         of examples, mention may be made of cyclopropyl, cyclobutyl,         cyclopentyl, cyclohexyl, etc., groups;     -   “a fluoroalkyl” is intended to mean: an alkyl group of which one         or more of the hydrogen atoms have been substituted with a         fluorine atom;     -   “an alkoxy” is intended to mean: an —O-alkyl radical where the         alkyl group is as defined above;     -   “a fluoroalkoxy” is intended to mean: an alkoxy group of which         one or more hydrogen atoms have been substituted with a fluorine         atom;     -   “a thioalkyl or alkylthio” is intended to mean: an —S-alkyl         radical where the alkyl group is as defined above;     -   “an aryl” is intended to mean: a monocyclic or bicyclic aromatic         group containing between 6 and 10 carbon atoms. By way of         examples of aryl groups, mention may be made of phenyl or         naphthyl groups;     -   “a heterocycle” is intended to mean: a 5- to 17-membered,         saturated or partially unsaturated, mono-cyclic, bicyclic or         tricyclic group containing from 1 to 8 heteroatoms selected from         O, S and N.

By way of examples of a monocyclic heterocycle, mention may be made of azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, dihydropyrrolyl or tetrahydropyridinyl groups;

by way of examples of a bicyclic heterocycle, mention may be made of indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolinyl, dihydroisobenzofuranyl, dihydrobenzimidazolyl, dihydro-isobenzothiazolyl, dihydroquinolinyl, tetrahydro-quinolinyl, dihydroisoquinolinyl, tetrahydroiso-quinolinyl, dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl, dihydroquinazolinyl, tetrahydro-quinazolinyl, dihydroquinoxalinyl, tetrahydro-quinoxalinyl, dihydrophthalazinyl, tetrahydro-phthalazinyl, tetrahydrobenzazepinyl, tetrahydro-benzo[1,4]diazepinyl, tetrahydrobenzo[1,4]oxazepinyl or tetrahydrobenzo[1,4]thiazepinyl groups; by way of examples of a tricyclic heterocycle, mention may be made of dihydroimidazo[1,2-a]benzimidazolyl, dihydropyrrolo[1,2-a]benzimidazolyl, tetrahydropyrido-[1,2-a]benzimidazolyl, dihydrothiazolo[1,2-a]-benzimidazolyl, tetrahydropyrimido[1,2-a]benzimidazolyl, tetrahydrodiazepino[1,3][1,2-a]benzimidazolyl, dihydrooxazino[1,4][4,3-a]benzimidazolyl or tetrahydropyrazino[1,2-a]benzimidazolyl groups;

-   -   “a heteroaryl” is intended to mean: a 5- to 14-membered aromatic         monocyclic, bicyclic or tricyclic group containing from 1 to 8         heteroatoms selected from O, S and N.

By way of examples of a monocyclic heteroaryl, mention may be made of imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl groups;

by way of examples of a bicyclic heteroaryl, mention may be made of indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzofuranyl, isobenzothiazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl or quinoxalinyl groups; by way of examples of a tricyclic heteroaryl, mention may be made of pyrido[1,2-a]benzimidazolyl, thiazolo[1,2-a]-benzimidazolyl, imidazo[1,2-a]benzimidazolyl, pyrimido[1,2-a]benzimidazolyl or pyrazino[1,2-a]-benzimidazolyl groups;

-   -   “oxo” signifies “═O”;     -   “thio” signifies “═S”.

Among the compounds of the invention, a first group of compounds comprises the compounds of formula (II)

in which:

X is a carbon atom or a nitrogen atom; said X being identical to or different from one another and the number of X═N not being greater than 2;

R₁, R₂, R₃, Y and A being as defined in formula (I), it being possible for R₁ to be linked to the 6-element or 5-element unit of the bicycle.

Among the compounds of the invention, a second group of compounds comprises the compounds of formula (III)

in which:

R_(1a) is one or more atoms or groups, which may be identical or different, selected from a hydrogen atom, a halogen atom or a C₁-C₆-alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-thioalkyl, C₁-C₆-alkyl-S(O)₂—, NR₄R₅ or nitro group;

R_(1b) is a hydrogen atom, or a C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, aryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl, R₄R₅NC(O)—C₁-C₃-alkylene, aryl, heteroaryl, aryl-C₁-C₆-alkylene or heteroaryl-C₁-C₆-alkylene group;

said heteroaryl or aryl groups of R_(1b) being optionally substituted with one or more substituents R₉, which may be identical to or different from one another;

R₉ is a halogen atom or a C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkyl, aryl, heteroaryl, NR₄R₅ or arylthio group, said heteroaryl or aryl groups being optionally substituted with one or more substituents selected from a halogen atom, and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkoxy, nitro, cyano or R₄R₅N—C₁-C₃-alkylene group;

R₂, R₃, R₄, R₅, A, X and Y being as defined in formula (II).

Among the compounds of the invention, a third group of compounds comprises the compounds of formula (IV):

in which W is a tricyclic heterocycle or a tricyclic heteroaryl selected from:

R₁, R₂, R₃, P and Y being as defined in formula (I).

Among the compounds of the invention, a fourth group of compounds comprises the compounds of formula (V)

in which:

R₁, R₂, R₃, A and P are as defined in formula (I).

Among the compounds of the invention, a fifth group of compounds comprises the compounds of formula (V) in which:

R₂ is a hydrogen atom, or a C₁-C₆-alkyl or C₁-C₆-alkoxy group;

R₃ is from one to three atoms or groups, which may be identical or different, selected from a hydrogen atom, and a C₁-C₆-alkyl, C₁-C₆-alkoxy or hydroxyl group, when R₃ is carried by a carbon atom;

or

R₃ is from one to two atoms or groups, which may be identical or different, selected from a hydrogen atom, and a C₁-C₆-alkyl, C₁-C₆-alkyl-O—C(O)— or aryl-C₁-C₃-alkyl-O—C(O)— group, when R₃ is carried by a nitrogen atom;

R₁, A and P being as defined in formula (I).

Among the compounds of the invention, a sixth group of compounds comprises the compounds of formula (V) in which:

A is, with the C—N bond of the benzimidazole unit with which it is fused, a 5- to 7-membered monocyclic heterocycle or monocyclic heteroaryl containing from one to three heteroatoms selected from O, S and N, including the nitrogen atom of the benzimidazole unit;

R₁, R₂, R₃ and P being as defined in formula (I).

Among the compounds of the invention, a seventh group of compounds comprises the compounds of formula (Va) in which:

A is, with the C—N bond of the benzimidazole unit with which it is fused, a 5- to 7-membered monocyclic heterocycle or monocyclic heteroaryl containing one or two heteroatoms selected from O, S and N, including the nitrogen atom of the benzimidazole unit;

X is a carbon atom or a nitrogen atom; said X being identical to or different from one another and the number of X═N not being greater than 1;

R_(1a) is one or more atoms or groups, which may be identical or different, selected from a hydrogen atom, a halogen atom, more particularly fluorine, bromine or chlorine, or a C₁-C₆-alkyl group, more particularly methyl, ethyl, isopropyl or tert-butyl, a C₁-C₆-fluoroalkyl group, more particularly trifluoromethyl, a C₁-C₆-alkoxy group, more particularly methoxy, a C₁-C₆-thioalkyl group, more particularly SCH₃, a C₁-C₆-alkyl-S(O)₂— group, more particularly —SO₂CH₃, an NR₄R₅ group or a nitro group;

R_(1b) is a hydrogen atom, or a C₁-C₆-alkyl, more particularly methyl, heteroaryloxy-C₁-C₆-alkyl, more particularly pyridinyloxyethyl, aryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl, more particularly benzyloxyethyl, R₄R₅NC(O)—C₁-C₃-alkylene, more particularly R₄R₅NC(O)CH₂—, aryl, more particularly phenyl, heteroaryl, more particularly pyridinyl, aryl-C₁-C₆-alkylene, more particularly benzyl or naphthylmethyl, phenylethyl, phenylpropyl, or heteroaryl-C₁-C₆-alkylene, more particularly pyridinylmethyl, pyridinylethyl, pyridinylpropyl, thiazolylmethyl, pyrimidinylmethyl, quinolinylmethyl, quinoxalinylmethyl, furanylmethyl, pyrazinylmethyl or benzothiazolylmethyl group;

said heteroaryl or aryl groups of R_(1b) being optionally substituted with one or more substituents R₉, which may be identical to or different from one another;

R₂ is a hydrogen atom;

R₃ is an atom or group selected from a hydrogen atom, a C₁-C₆-alkyl group, more particularly methyl, a C₁-C₆-alkoxy group, more particularly methoxy, or a hydroxyl group, when R₃ is carried by a carbon atom;

or

R₃ is an atom or group selected from a hydrogen atom, a C₁-C₆-alkyl group, more particularly methyl, and a C₁-C₆-alkyl-O—C(O)— group, more particularly (CH₃)₃C—O—C(O)—, when R₃ is carried by a nitrogen atom;

R₄ and R₅ are, independently of one another, a C₁-C₆-alkyl group, more particularly methyl or ethyl;

or R₄ and R₅ form, together with the nitrogen atom which carries them, a pyrrolidine or morpholine group;

R₉ is a halogen atom, more particularly fluorine or chlorine, or a C₁-C₆-alkyl, more particularly methyl, C₁-C₆-alkoxy, more particularly methoxy, C₁-C₆-fluoroalkyl, more particularly trifluoromethyl, aryl, more particularly phenyl, heteroaryl, more particularly imidazolyl, NR₄R₅, or arylthio, more particularly phenylthio, group, said aryl groups being optionally substituted with one or more C₁-C₆-alkyl groups, more particularly methyl.

Among the compounds of the invention, an eighth group of compounds comprises the compounds of formula (I) in which at the same time R₁ and/or R₂ and/or R₃, and/or A, and/or P and/or Y are as defined in the groups above.

Among the compounds of the invention, a ninth group of compounds comprises the compounds of formula (I′)

in which

-   A is, with the C—N bond of the benzimidazole unit with which it is     fused, a 4- to 7-membered monocyclic heterocycle or monocyclic     heteroaryl containing from 1 to 3 heteroatoms chosen from O, S and     N, including the nitrogen atom of the benzimidazole unit; -   P is an 8-, 9-, 10- or 11-membered bicyclic hetero-cycle or bicyclic     heteroaryl containing from 1 to 6 heteroatoms selected from N, O and     S;     -   with the proviso that, when A is a 7-membered saturated         heterocycle, P is different from the         2,3-dihydro-1,4-benzodioxane group and from the         1-benzopyran-2-one group; -   R₁ is from 1 to 4 atoms or groups, which may be identical or     different, selected from a hydrogen atom, a halogen atom, and an     oxo, thio, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,     C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,     C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy,     C₁-C₆-fluoroalkoxy, cyano, C(O)NR₄R₅, nitro, NR₄R₅, C₁-C₆-thioalkyl,     C₃-C₇-cycloalkylthio, C₃-C₇-cycloalkyl-C₁-C₃-alkylenethio,     —S(O)—C₁-C₆-alkyl, —S(O)—C₃-C₇-cycloalkyl,     —S(O)—C₁-C₃-alkylene-C₃-C₇-cycloalkyl, C₁-C₆-alkyl-S(O)₂—,     C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—,     C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, SO₂NR₄R₅, NR₆C(O)R₇,     NR₆SO₂R₈, R₄R₅NC(O)—C₁-C₃-alkylene, aryl, heteroaryl,     aryl-C₁-C₅-alkylene, heteroaryl-C₁-C₅-alkylene, aryloxy, arylthio,     heteroaryloxy or heteroarylthio group, said heteroaryl or aryl     groups being optionally substituted with one or more substituents     selected from a halogen atom, and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,     C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,     C₁-C₆-fluoroalkoxy, nitro, cyano, NR₄R₅ or R₄R₅N—C₁-C₃-alkylene     group;     -   with the proviso that, when R₁ is attached to a nitrogen atom of         P, then R₁ is different from a halogen atom, and from an oxo,         thio, cyano, nitro, NR₄R₅, C₁-C₆-thioalkyl, thioaryl,         thioheteroaryl, C₁-C₆-alkoxy, aryloxy, heteroaryloxy, —NR₆COR₇         and —NR₆SO₂R₈ group; -   Y is an oxygen or sulphur atom; -   R₂ is a hydrogen atom, a halogen atom, or a C₁-C₆-alkyl,     C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl     or C₁-C₆-alkoxy group; -   R₃ is from 1 to 3 atoms or groups, which may be identical or     different, selected from a hydrogen atom, a halogen atom,     C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,     C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy and     C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy, when R₃ is carried by a carbon     atom; -   or     -   is from 1 to 2 atoms or groups, which may be identical or         different, selected from a hydrogen atom, a halogen atom, and a         C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,         C₁-C₆-fluoroalkyl, aryl-C(O)—, C₁-C₆-alkyl-C(O)—,         C₃-C₇-cycloalkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-C(O)—,         C₁-C₆-fluoroalkyl-C(O)—, aryl-S(O)₂—, C₁-C₆-alkyl-S(O)₂—,         C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cyclo-alkyl-S(O)₂—,         C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, C₁-C₆-alkyl-O—C(O)—,         C₃-C₇-cycloalkyl-O—C(O)—,         C₃-C₇-cycloalkyl-C₁-C₃-alkylene-O—C(O)—,         C₁-C₆-fluoroalkyl-O—C(O)—, aryl-O—C(O)— or heteroaryl-O—C(O)—         group, when R₃ is carried by a nitrogen atom; -   R₄ and R₅ are, independently of one another, a hydrogen atom or a     C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,     aryl-C₁-C₅-alkylene or aryl group; -   or R₄ and R₅ form, together with the nitrogen atom which carries     them, an azetidine, pyrrolidine, piperidine, azepine, morpholine,     thiomorpholine, piperazine or homopiperazine group, this group being     optionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,     C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene, aryl,     heteroaryl, aryl-S(O)₂—, C₁-C₆-alkyl-S(O)₂—,     C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—,     C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, aryl-C(O)—,     C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—,     C₃-C₇-cycloalkyl-C₁-C₃-alkylene-C(O)— or C₁-C₆-fluoroalkyl-C(O)—     group; -   R₆ and R₇ are, independently of one another, a hydrogen atom, or a     C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-,     aryl-C₁-C₆-alkylene- or aryl group; -   R₈ is a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,     C₃-C₇-cycloalkyl-C₁-C₃-alkylene-, aryl-C₁-C₆-alkylene- or aryl     group.

Among the compounds of the invention, a tenth group of compounds comprises the compounds of formula (II′) in which

in which

-   X is a carbon atom or a nitrogen atom; said X being identical to or     different from one another and the number of X═N not being greater     than 2; -   R₁, R₂, R₃, Y and A being as defined in formula (I); it being     possible for R₁ to be linked to the 5- or 6-element unit of the     bicycle.

Among the compounds of the invention, an eleventh group of compounds comprises the compounds of formula (III′)

in which

-   R_(1a) is one or more atoms or groups, which may be identical or     different, selected from a hydrogen atom, a halogen atom or a     C₁-C₆-fluoroalkyl group; -   R_(1b) is a hydrogen atom, or a C₁-C₆-alkyl, aryl, hetero-aryl,     aryl-C₁-C₆-alkylene- or heteroaryl-C₁-C₆-alkylene- group, said     groups being optionally substituted with one or more groups or     atoms, which may be identical or different, selected from a halogen     atom or a C₁-C₆-alkyl group; -   R₂, R₃, A, X and Y being as defined in formula (II).

Among the compounds of the invention, a twelfth group of compounds comprises the compounds of formula (IV′):

in which W is a tricyclic heterocycle or a tricyclic heteroaryl selected from:

R₁, R₂, R₃, P and Y being as defined in formula (I).

Among the compounds of the invention, a thirteenth group of compounds comprises the compounds of formula (V′),

in which

R₁, R₂, R₃, A, P and Y are as defined in formula (I).

Among the compounds of the invention, a fourteenth group of compounds comprises the compounds of formula (V′) in which

R₂ and R₃ are, independently of one another, a hydrogen atom or a C₁-C₆-alkyl group;

R₁, A, P and Y being as defined in formula (I).

Among the compounds of the invention, a fifteenth group of compounds comprises the compounds of formula (I) in which at the same time R₁ and/or R₂ and/or R₃, and/or A, and/or P and/or Y are as defined in the groups 9 to 14 above.

In the subsequent text, the term “leaving group” is intended to mean a group that can be readily cleaved from a molecule through the breaking of a heterolytic bond, with the departure of a pair of electrons. This group can thus be readily replaced with another group during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxyl group such as a methanesulphonate, benzenesulphonate, p-toluenesulphonate, triflate, acetate, etc. Examples of leaving groups and also references for the preparation thereof are given in “Advances in Organic Chemistry”, J. March, 5th Edition, Wiley Interscience, 2001.

In the subsequent text, the term “protective group” is intended to mean a group that can be momentarily incorporated into a chemical structure with the aim of temporarily inactivating a part of the molecule during a reaction, and that can be readily removed at a subsequent step of the synthesis. Examples of protective groups and also references regarding their properties are given in T. W. Greene, P. G. M. Wutz, 3rd Edition, Wiley Interscience 1999.

In accordance with the invention, the compounds of formula (I) can be prepared according to the process illustrated by general scheme 1 which follows:

The compounds (I) can be obtained by reaction of a compound of formula (VI) in which B is a C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy or aryl-C₁-C₃-alkylenoxy group, and P, Y and R₁ are as defined in formula (I), with an amide of the compound of formula (VII), in which A, R₂ and R₃ are as defined in formula (I) above, at the reflux of a solvent such as toluene. The aluminum amide of the compound of formula (VII) is prepared by the prior action of trimethylaluminum on the amines of formula (VII).

Starting from compounds of formula (VI), in which B is a hydroxyl group, and P, Y and R₁ are as defined in formula (I), the carboxylic acid function can be converted beforehand to an acid halide such as an acid chloride by the action, for example, of thionyl chloride, at the reflux of a solvent such as dichloromethane or dichloroethane. The compound of formula (I) is then obtained by reaction of the compounds of formula (VI), in which B is a chlorine atom, and P, Y and R₁ are as defined in formula (I), with the compound of formula (VII), in which A, R₂ and R₃ are as defined in formula (I) above, in the presence of a base such as triethylamine or sodium carbonate.

Alternatively, the compounds of formula (VI), in which B is a hydroxyl group, and P, Y and R₁ are as defined in formula (I), can be coupled with the compounds of formula (VII) in the presence of a coupling agent such as a dialkylcarbodiimide, [(benzotriazol-1-yl)oxy][tris(pyrrolidino)]phosphonium hexafluorophosphate, diethylcyanophosphonate or any other coupling agent known to those skilled in the art, in the presence of a base such as triethylamine, in a solvent such as, for example, dimethylformamide.

In scheme 1, the compounds of formulae (VI) and (VII) and the other reagents, when the method of preparing them is not described, are commercially available, described in the literature, or prepared by analogy to processes described in the literature (R. S. Begunov et al., Russian J. Org. Chem., 2004, 40(11), 1740-1742; V. M. Reddy et al., J. Indian Chem. Soc., 1984, (111), 89-91; K. V. B. Rao et al., Eur. J. Med. Chem., 1981, 16(1), 35-38; R. J. North et al., J. Het. Chem., 1969, 6, 655; A. R. Freedman et al., J. Het. Chem., 1966, 3(3), 257; Mullock, E. B. J. Chem. Soc. Section C, 1970, (6), 829-833), for example.

The compounds of formula (VI) or (I), that are C-substituted on an aryl or heteroaryl group with an alkyl group, can be obtained by a coupling reaction, catalyzed by a metal such as palladium or iron, carried out on the corresponding compounds of formula (VI) or (I), substituted with a halogen atom, such as a chlorine, in the presence, for example, of an alkylmagnesium halide or of an alkylzinc halide, according to the methods described in the literature (A. Furstner et al., J. Am. Chem. Soc., 2002, 124(46), 13856; G. Quéguiner et al., J. Org. Chem., 1998, 63(9), 2892), for example, or known to those skilled in the art.

The compounds of formula (VI) or (I), that are C-substituted on an aryl or heteroaryl group with a cyano, aryl or heteroaryl group, can be obtained by a coupling reaction, catalyzed by a metal such as palladium, carried out on the corresponding compounds of formula (VI) or (I), substituted, for example, with a bromine atom, in the presence of trimethylsilyl cyanide, of arylboronic acid or of heteroarylboronic acid, or by any other method described in the literature or known to those skilled in the art.

The compounds of formula (VI) or (I), in which P is N-substituted with a substituent R₁ corresponding to an aryl or heteroaryl group, can be obtained by a coupling reaction, catalyzed by a metal such as copper, carried out on the corresponding amines of formula (VI) or (I), in the presence of an aryl halide or a heteroaryl halide, according to the Buchwald method (S. L. Buchwald et al., J. Am. Chem. Soc., 2002, 124, 11684), or by any other method described in the literature or known to those skilled in the art.

The compounds of formula (I) or (VI), that are C-substituted on an aryl or heteroaryl group with an NR₄R₅, NR₆COR₇ or NR₆SO₂R₈ group, can be obtained from the corresponding compounds of formula (I) or (VI), substituted, for example, with a bromine atom, by a coupling reaction respectively with an amine, an amide or a sulphonamide in the presence of a base, of a phosphine and of a palladium-based catalyst, according to methods described in the literature or known to those skilled in the art.

The compounds of formula (I) or (VI), that are substituted with a C(O)NR₄R₅ group, can be obtained from the corresponding compounds of formula (I) or (VI), substituted with a cyano group, according to methods described in the literature or known to those skilled in the art.

The compounds of formula (I) or (VI), that are substituted with an —S(O)-alkyl or —S(O)₂-alkyl group, can be obtained by oxidation of the corresponding compounds of formula (VI) or (I), substituted with a thioalkyl group, according to methods described in the literature or known to those skilled in the art.

The compounds of formula (VI) or (I), that are substituted with an NR₄R₅, NR₆COR₇ or NR₆SO₂R₈ group, can be obtained from the corresponding compounds of formula (VI) or (I), substituted with a nitro group, for example by reduction, then acylation or sulphonylation, according to methods described in the literature or known to those skilled in the art.

The compounds of formula (VI) or (I), that are substituted with an SO₂NR₄R₅ group, can be obtained by a method similar to that described in Pharmazie, 1990, 45, 346, or according to methods described in the literature or known to those skilled in the art.

The compounds of formula (I) or (VI) in which Y is a sulphur atom can, for example, be obtained by reaction of the corresponding compounds of formula (I) or (VI) in which Y is an oxygen atom, with a reagent such as Lawesson's reagent.

The compounds of formula (I) for which R₃ corresponds to a protective group carried by a nitrogen, such as an ethoxycarbonyl group, a tert-butyloxycarbonyl group or a benzyloxycarbonyl group, can be deprotected, according to chemical methods known to those skilled in the art, so as to give compounds of formula (I) where R₃ is a hydrogen atom.

A subject of the invention, according to another of its aspects, is also the compounds of formula (VII-x) with x ranging from a to n. These compounds can be used as synthesis intermediates of the compounds of formula (I).

The amines (VII-b), (VII-j), (VII-k) and (VII-l) can be prepared according to scheme 2 hereinafter:

Scheme 2

No. R3 VII-b 1-Me VII-j 3-OH VII-k 2-OH VII-l 2-OMe

A process for preparing the amines (VII-b), (VII-j), (VII-k) and (VII-l), in their racemic forms, is summarized in scheme 2. It consists, in a first step, in substituting 2-fluoro-5-nitroaniline (IX) with the racemic amine (VIII). This reaction is carried out, for example, by heating the two reagents without solvent. The addition products (X) thus obtained are subsequently cyclized to heterocycles (XI) in the presence of a reagent such as trifluoroacetic acid and of a reagent such as hydrogen peroxide, the reaction being carried out in solution in a solvent such as dichloromethane (by optimization of a process described in A. R. Freedman et al., J. Het. Chem., 1966, 3(3), 257). In the case where R₃ is different from a hydrogen atom, the cyclization can give a mixture of regioisomers.

The compound (XI) (R₃=hydroxyl) can be converted to the compound (XII) with R₃=methoxy, for example by alkylation in the presence of a base such as sodium hydride and of an alkylating agent such as methyl iodide or dimethyl sulphate. The nitro group of the compound (XI) or (XII) is subsequently reduced to give the amines (VII-b), (VII-j), (VII-k) or (VII-l), by catalytic hydrogenation in the presence of a catalyst such as palladium-on-charcoal, or by any other method of reduction of a nitro group to an amine, known to those skilled in the art.

The amines (VII-e) and (VII-f) can be prepared according to scheme 3 hereinafter:

A process for preparing the amines (VII-e) and (VII-f) consists, in a first step, in substituting 2-fluoro-5-nitroaniline (IX) with piperazine (XIII), which is substituted on one of the nitrogens with a protective group G. This reaction is carried out, for example, by heating the two reagents without solvent. The addition product (XIV) thus obtained is subsequently cyclized to a heterocyclic compound (XV) in the presence of a reagent such as trifluoroacetic acid or formic acid and of a reagent such as hydrogen peroxide, the reaction being carried out in solution in a solvent such as dichloromethane. The heterocyclic compound (XV) can then be deprotected; for example, if G=CO₂CH₃, the hydrolysis of (XV) in the presence of an acid such as hydrochloric acid gives the amine (XVI) which can be alkylated, for example in the presence of a base such as sodium hydride and of an alkylating agent such as methyl iodide, in a solvent such as tetrahydrofuran or dimethylformamide, to give the heterocycle (XVII). The nitro group of the compound (XVII) is subsequently reduced to give the amine (VII-e) by catalytic hydrogenation in the presence of a catalyst such as palladium-on-charcoal, or by any other method of reduction of a nitro group to an amine, known to those skilled in the art. The amine (VII-f) is prepared by reducing the nitro group of the compound (XV), for example if G=CO₂CH₂Ph, by reaction with a reagent such as tin chloride, in a solvent such as dimethylformamide.

The amines (VII-a), (VII-c) and (VII-d) can be prepared according to scheme 4 hereinafter:

The amine (VII-a) can be prepared by reduction of a corresponding nitro precursor (XVIII), described in the literature (R. J. North et al., J. Het. Chem., 1969, 6, 655), for example, by catalytic hydrogenation in the presence of a catalyst such as palladium-on-charcoal, or according to any other method of reduction of a nitro group to an amine, known to those skilled in the art.

The amine (VII-c) can be prepared in two steps from the nitro precursor (XVIII) described above. The intermediate (XIX) is prepared from the precursor (XVIII), using a base such as sodium hydride and an alkylating agent such as methyl iodide, in a solvent such as tetrahydrofuran or dimethylformamide. The compound (XIX) thus obtained can subsequently be converted to an amine (VII-c) by catalytic hydrogenation in the presence of a catalyst such as palladium-on-charcoal, or by any other method of reduction of a nitro group to an amine, known to those skilled in the art.

The amine (VII-d) can be prepared in two steps from the nitro precursor (XVIII) described above. The intermediate (XX) is prepared from the precursor (XVIII), using a base such as sodium hydride and di-tert-butyl dicarbonate. The compound (XX) thus obtained can subsequently be converted to an amine (VII-d) by catalytic hydrogenation in the presence of a catalyst such as palladium-on-charcoal, or by any other method of reduction of a nitro group to an amine, known to those skilled in the art.

The amine (VII-g) can be prepared according to scheme 5 hereinafter:

The amine (VII-g) can be prepared in two steps from 2-iodo-4-nitrochlorobenzene (XXI) (G. A. Olah, J. Org. Chem., 1993 (58), 3194-3195). Firstly, the compound (XXI) reacts with aminopyrazine (XXII) in the presence of a catalyst such as palladium diacetate, of a phosphine and of a base such as cesium carbonate, in a solvent such as toluene. Under these conditions, the cyclization product (XXIII) is isolated and can finally give the amine (VII-g) by catalytic hydrogenation in the presence of a catalyst such as palladium-on-charcoal, or according to any other method of reduction of a nitro group to an amine, known to those skilled in the art.

The amines (VII-h) and (VII-i) can be prepared according to scheme 6 hereinafter:

The condensation of 2-amino-5-nitrobenzimidazole (XXIV) with a reagent such as diacetal (XXV) makes it possible to isolate a cyclization product (XXVI), which is a mixture of two isomers. The nitro group of the hetero-cycle (XXVI) can be reduced to an amine group by reaction with tin chloride, or according to any other method of reduction of a nitro group to an amine, known to those skilled in the art. The amines (VII-h) and (VII-i) are thus obtained.

The amines (VII-m) and (VII-n) can be prepared according to scheme 7 hereinafter:

The amines (VII-m) and (VII-n) can be prepared in four steps from formamide (XXVII) (S. L. Chupak, US2006135447). The formamide (XXVII) can be activated in the form of dichloroimine (XXVIII) by reaction with a mixture of SOCl₂ and SO₂Cl₂. The compound (XXVIII) can subsequently be substituted with a diamine of structure (XXIX), in which n=3 or 4, to give a compound of structure (XXX). The latter can subsequently be converted to a tricyclic benzimidazole (XXXI) in the presence of a catalyst such as palladium diacetate, of a phosphine and of a base such as cesium carbonate. Reduction of the nitro group of (XXXI) by catalytic hydrogenation in the presence of a catalyst such as palladium-on-charcoal, or according to any other method of reduction of a nitro group to an amine, known to those skilled in the art, makes it possible to obtain the amine (VII-m) or (VII-n).

The table which follows illustrates the chemical structures and the physical properties of some examples of intermediate compounds of formula (VII) according to the invention.

In this table:

-   -   the column “Mp (° C.)” gives the melting points of the products         in degrees Celsius (° C.), failing this “NMR” indicates that the         NMR spectrum is described in the examples;     -   in the “salt/base” column, “-” represents a compound in free         base form, whereas “HCl” represents a compound in hydrochloride         form and the ratio between brackets is the (acid:base) ratio.

TABLE 1 No. structure Salt/Base Mp (° C.) VII-a

— 235-236 VII-b

— 168-172 VII-c

— 195-190 VII-d

— 198-200 VII-e

— NMR (Example V) VII-f

— 115-118 VII-g

— 249-253 VII-h

— NMR (Example VIII-2) VII-i

— NMR (Example VIII-3) VII-j

— NMR (Example X-3) VII-k

HCl (1:1) NMR (Example X-4) VII-l

— 140-142 VII-m

HCl (1:1) 335-340 VII-n

HCl (2:1) 330-336

The following examples describe the preparation of some intermediate compounds of formula (VII) in accordance with the invention. The numbers of the compounds exemplified refer to those in Table 1. The elemental microanalyses, the LC-MS (liquid chromatography-mass spectrometry) analyses, or the IR or NMR spectra confirm the structures of the compounds obtained.

EXAMPLE I Compound No. VII-a 6-amino-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole

1 g of palladium-on-charcoal at 10% is added, under argon, to a vigorously stirred solution of 2.7 g (13.22 mmol) of 2,3-dihydro-6-nitro-1H-imidazo[1,2-a]-benzimidazole (R. J. North et al., J. Het. Chem., 1969, 6, 655) in 100 ml of methanol. 15 g (0.23 mol) of ammonium formate are added to the reaction mixture and the suspension is subsequently stirred for 12 h. A solid is recovered by filtration and is purified by silica column chromatography (eluent: dichloromethane-methanol). 0.82 g of the expected product is obtained in the form of a grey solid after drying under reduced pressure.

Melting point (base): 235-236° C.

¹H NMR (DMSO D₆), δ (ppm): 3.89 (m, 4H); 4.38 (m, 2H); 6.18 (dxd, 1H); 6.46 (d, 1H); 6.58 (s, 1H); 6.73 (d, 1H).

EXAMPLE II Compound No. VII-b 6-amino-2,3-dihydro-1-methyl-1H-pyrrolo[1,2-a]-benzimidazole II-1 2-(2-methylpyrrolidin-1-yl)-5-nitroaniline

5 g (32.03 mmol) of 2-fluoro-5-nitroaniline and 4.9 ml (48.04 mmol) of 2-methylpyrrolidine (racemic) are placed in a screw reactor. The reactor is closed and the mixture is heated at 100° C. for 5 h. After cooling, the mixture is taken up with 100 ml of water and 100 ml of dichloromethane. The organic phase is separated, washed with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. The resulting product is used as it is in the subsequent reaction.

II-2 2,3-dihydro-1-methyl-6-nitro-1H-pyrrolo[1,2-a]-benzimidazole

2 ml (22.6 mmol) of a 35% aqueous solution of hydrogen peroxide are added, dropwise, to a solution of 1 g (4.52 mmol) of 2-(2-methylpyrrolidin-1-yl)-5-nitro-aniline, obtained in the preceding step, and 4 ml (51.92 mmol) of trifluoroacetic acid in 20 ml of dichloromethane. The mixture is refluxed for 30 min and then cooled and taken up in 100 ml of dichloromethane and 100 ml of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is separated, washed with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. The resulting orange oil (0.89 g) is used as it is in the subsequent reaction.

II-3 6-amino-2,3-dihydro-1-methyl-1H-pyrrolo[1,2-a]-benzimidazole (VIIb)

A mixture of 0.25 g (1.15 mmol) of 2,3-dihydro-1-methyl-6-nitro-1H-pyrrolo[1,2-a]benzimidazole, obtained in the preceding step, and 10 mg of palladium-on-charcoal at 10%, in suspension in 15 ml of ethanol and 1 ml of a 1N aqueous solution of hydrochloric acid, is stirred for four hours at ambient temperature under 4 bar of hydrogen. After this period of time, the mixture is filtered, concentrated under reduced pressure, and taken up with 100 ml of dichloromethane and 100 ml of a 30% aqueous solution of sodium hydroxide. The organic phase is separated, washed with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. The resulting solid is purified by silica column chromatography (eluent: dichloromethane-methanol). 0.133 g of the expected product is obtained in the form of a beige solid after drying under reduced pressure.

Melting point (base): 168-172° C.

¹H NMR (DMSO D₆), δ (ppm): 1.49 (d, 3H); 2.16 (m, 1H); 2.75 (m, 1H); 2.9 (m, 2H); 3.2 (m, 2H); 4.41 (sext., 1H); 6.51 (dxd, 1H), 6.92 (d, 1H); 7.08 (d, 1H).

EXAMPLE III 6-amino-2,3-dihydro-3-methyl-1H-imidazo-1,2-a]benzimidazole (Compound No. VII-c) III-1 2,3-dihydro-3-methyl-6-nitro-1H-imidazo[1,2-a]-benzimidazole (Compound XIX)

0.1 g (0.49 mmol) of 2,3-dihydro-6-nitro-1H-imidazo[1,2-a]benzimidazole (R. J. North et al., J. Het. Chem., 1969, 6, 655) in 10 ml of tetrahydrofuran is added, under argon, to a suspension, stirred at 20° C., of 0.023 g (0.59 mmol) of sodium hydride at 60% in 5 ml of tetrahydrofuran. After stirring at 20° C. for 45 minutes, 30 μl (0.54 mmol) of iodomethane are added and the mixture is then stirred at 20° C. for 12 hours. After this period of time, the reaction mixture is poured into 100 ml of water and then extracted with three times 30 ml of dichloromethane. The organic phases are combined, dried over sodium sulphate, and then concentrated under reduced pressure. 0.1 g of the expected product (XIX) is thus obtained in the form of a yellow solid which will be used as it is in the subsequent synthesis.

Melting point (base): 208-209° C.

III-2 6-amino-2,3-dihydro-3-methyl-1H-imidazo[1,2-a]-benzimidazole (Compound No. VII-c)

0.5 g of palladium-on-charcoal at 10% is added, under argon, to a vigorously stirred solution of 0.81 g (3.71 mmol) of compound (XIX), prepared in the preceding step, in 70 ml of methanol. 10 g (0.153 mol) of ammonium formate are added to the reaction mixture and the suspension is subsequently stirred for 12 h. A solid is collected by filtration and is purified by silica column chromatography (eluent: dichloromethane-methanol). 0.26 g of the expected product is obtained in the form of a grey solid after drying under reduced pressure.

Melting point (base): 185-190° C.

¹H NMR (DMSO D₆), δ (ppm): 2.84 (s, 3H); 3.76 (m, 2H); 3.91 (m, 2H); 4.41 (s, NH₂); 6.19 (dxd, 1H); 6.48 (d, 1H); 7.71 (d, 1H).

EXAMPLE IV 6-amino-2,3-dihydro-3-tert-butoxycarbonyl-1H-imidazo[1,2-a]benzimidazole Compound No. VII-d IV-1 6-nitro-2,3-dihydro-3-tert-butoxycarbonyl-1H-imidazo[1,2-a]benzimidazole (Compound No. XX)

13.9 g (57.86 mmol) of 2,3-dihydro-6-nitro-1H-imidazo[1,2-a]benzimidazole (R. J. North et al., J. Het. Chem., 1969, 6, 655) are added, in several steps, to a suspension, stirred at 20° C. under argon, of 3.47 g (86.8 mmol) of sodium hydride at 60% in 482 ml of tetrahydrofuran. After stirring at 20° C. for 2 hours, 15.1 ml (65.73 mmol) of di-tert-butyl dicarbonate are added and the mixture is then stirred for 1 h 30 at 20° C. After this period of time, the reaction mixture is poured into 50 ml of water. A precipitate is collected by filtration and is dried under reduced pressure. 14.31 g of the expected product (XX) are thus obtained in the form of a yellow solid that will be used as it is in the subsequent synthesis.

Melting point (base): 222-224° C.

IV-2 6-amino-2,3-dihydro-3-tert-butoxycarbonyl-1H-imidazo[1,2-a]benzimidazole (Compound No. VII-d)

A suspension of 0.1 g (0.33 mmol) of compound (XX) and 0.5 g of palladium-on-charcoal at 10% in 150 ml of ethanol is stirred at 20° C. under 5 bar of hydrogen for four hours. After removal of the insoluble material by filtration, the resulting ethanolic solution is concentrated under reduced pressure. 70 mg of the expected product are thus obtained in the form of a white solid.

Melting point (base): 198-200° C.

¹H NMR (CDCl₃), δ (ppm): 1.51 (s, 9H); 2.25-3.55 (broad peak, NH₂); 4.01 (m, 2H); 4.32 (m, 2H); 6.48 (dxd, 1H); 6.83 (d, 1H); 6.91 (d, 1H)

EXAMPLE V 7-amino-3-methyl-1,2,3,4-tetrahydropyrazino-[1,2-a]benzimidazole (Compound No. VII-e) V-1 2-[4-(ethoxycarbonyl)pyrazin-1-yl]-5-nitroaniline (Compound No. XIV, G=CO₂Et)

A mixture of 10 g (64.06 mmol) of 2-fluoro-5-nitroaniline and 20.08 ml (137.72 mmol) of N-(ethoxy-carbonyl)piperazine is heated at 140° C. for 12 h. After this period of time, the mixture is concentrated under reduced pressure and then 5 ml of acetic acid are added. A precipitate is collected by filtration and is washed with water and then dried under reduced pressure. 18.5 g of the expected product are thus isolated in the form of a yellow solid.

¹H NMR (DMSO D₆), δ (ppm): 1.15 (t, 3H); 2.82 (m, 4H); 3.51 (m, 4H); 4.02 (q, 2H); 5.35 (s, NH₂); 6.95 (d, 1H); 7.38 (dxd, 1H); 7.5 (d, 1H).

V-2 3-ethoxycarbonyl-7-nitro-1,2,3,4-tetrahydro-pyrazino[1,2a]benzimidazole (Compound No. XV, G=CO₂Et)

15 ml (169.5 mmol) of an aqueous solution of hydrogen peroxide at 35% are added, dropwise, to a solution of 17 g (57.76 mmol) of the compound (XIV) obtained in the preceding step, and of 60 ml (51.92 mmol) of formic acid. The mixture is heated for one hour at 50° C. and then cooled, concentrated under reduced pressure, and taken up in 200 ml of dichloromethane and 300 ml of a saturated aqueous solution of potassium bicarbonate. The organic phase is separated, washed with 100 ml of a saturated solution of sodium chloride, dried over sodium sulphate and then concentrated under reduced pressure. The resulting foam is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 3.9 g of the expected compound are thus isolated in the form of a solid that will be used as it is in the subsequent synthesis.

V-3 7-nitro-1,2,3,4-tetrahydropyrazino[1,2-a]-benzimidazole (Compound No. XVI)

A solution of 3.9 g (13.44 mmol) of compound (XV), obtained in the preceding step, in 100 ml of 6N hydrochloric acid is refluxed for 12 hours. After this period of time, the cooled solution is brought to pH>9 by successive additions of concentrated sodium hydroxide, and then extracted three times with 100 ml of dichloromethane. The organic phases are combined, washed with 150 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The resulting product is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 0.3 g of the expected compound is thus isolated in the form of a solid that will be used as it is in the subsequent synthesis.

¹H NMR (CDCl₃), δ (ppm): 1.91 (1 broad peak, NH); 5.56 (m, 2H); 4.28 (m, 2H); 4.48 (s, 2H); 7.5 (d, 1H); 8.31 (dxd, 1H); 8.72 (d, 1H).

V-4 3-methyl-7-nitro-1,2,3,4-tetrahydropyrazino-[1,2-a]benzimidazole (Compound No. XVII)

0.3 g (1.37 mmol) of compound (XVI), obtained in the preceding step, in 20 μl (1.65 mmol) of iodomethane is added, under argon, to a suspension, stirred at 20° C., of 0.07 g (1.65 mmol) of sodium hydride at 60% in 15 ml of tetrahydrofuran, and then the mixture is stirred at 20° C. for 12 hours. After this period of time, the reaction mixture is poured into 100 ml of water and then extracted with three times 30 ml of dichloromethane. The organic phases are combined, dried over sodium sulphate, and then concentrated under reduced pressure. 0.13 g of the expected product (XVII) is thus obtained and will be used as it is in the subsequent synthesis.

¹H NMR (CDCl₃), δ (ppm): 2.49 (s, 3H); 2.93 (m, 2H); 3.82 (s, 2H); 4.11 (m, 2H); 7.29 (d, 1H); 8.09 (dxd, 1H); 8.49 (d, 1H).

V-5 7-amino-3-methyl-1,2,3,4-tetrahydropyrazino-[1,2-a]benzimidazole (Compound No. VII-e)

A suspension of 0.13 g (0.56 mmol) of compound (XVII) obtained in the preceding step, of 0.2 g of palladium-on-charcoal at 10% and of 5 g (79.36 mmol) of ammonium formate is stirred at 20° C. for 12 hours. After removal of the insoluble material by filtration, the filtrate is concentrated under reduced pressure. 80 mg of the expected product are thus obtained in the form of an oil.

¹H NMR (CDCl₃), δ (ppm): 2.48 (s, 3H); 2.89 (m, 2H); 3.75 (s, 2H); 3.85 (broad peak, NH₂); 3.97 (m, 2H); 6.57 (dxd, 1H); 6.91 (d, 1H); 7 (d, 1H).

EXAMPLE VI 7-amino-3-benzyloxycarbonyl-1,2,3,4-tetra-hydropyrazino[1,2-a]benzimidazole (Compound No. VII-f) VI-1 2-[4-(benzyloxycarbonyl)pyrazin-1-yl]-5-nitro-aniline (Compound No. XIV, G=CO₂CH₂Ph)

A mixture of 9.44 g (60.5 mmol) of 2-fluoro-5-nitro-aniline and 24.98 ml (130.08 mmol) of N-(benzyloxy-carbonyl)piperazine is heated at 140° C. for 12 h. After this period of time, the mixture is taken up in 200 ml of dichloromethane. The organic phase is successively washed with a saturated aqueous solution of potassium carbonate, and three times with 50 ml of water, and is then dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and ethyl acetate. 8.6 g of the expected product are thus isolated.

¹H NMR (CDCl₃), δ (ppm): 2.91 (m, 4H); 3.68 (m, 4H); 4.16 (s, NH₂); 5.18 (s, 2H); 6.92 (d, 1H); 7.35 (m, 5H); 7.6 (m, 2H).

VI-2 3-benzyloxycarbonyl-7-nitro-1,2,3,4-tetrahydro-pyrazino[1,2-a]benzimidazole (Compound No. XV, G=CO₂CH₂Ph)

17.7 ml (0.2 mol) of an aqueous solution of hydrogen peroxide at 35% are added, dropwise in two hours, to a solution, stirred at 0° C., of 8.6 g (24.13 mmol) of 2-[4-(benzyloxycarbonyl)pyrazin-1-yl]-5-nitroaniline obtained in the preceding step and 34.4 ml (29.4 mmol) of formic acid. The mixture is stirred for 3 hours at 0° C. and for 12 hours at 20° C. and is then poured over 300 g of ice. The pH of the medium is adjusted to 8 by adding an aqueous ammonia solution, and then extracted with 200 ml of dichloromethane. The organic phase is washed with 100 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. A residue is obtained, which is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and ethyl acetate. 1.2 g of the expected product are thus isolated. ¹H NMR (CDCl₃), δ (ppm): 4.11 (m, 2H); 4.21 (m, 2H); 5.05 (s, 2H); 5.18 (s, 2H); 7.38 (m, 6H); 8.21 (dxd, 1H); 8.61 (d, 1H).

VI-3 7-amino-3-benzyloxycarbonyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]benzimidazole (Compound No. VII-f)

7.68 g (34.06 mmol) of tin chloride dihydrate are added, in several steps, to a solution, in 56 ml of dimethylformamide, of 2 g (5.68 mmol) of compound (XV), obtained in the preceding step, and of 2.6 g (8.85 mmol) of tetrabutylammonium bromide. The mixture is stirred at 20° C. for 24 hours and then concentrated and taken up with 100 ml of water. The pH of the solution thus obtained is adjusted to 9 by adding an aqueous ammonia solution. The mixture is subsequently extracted twice with 100 ml of ethyl acetate. The organic phases are combined, washed twice with 50 ml of water and once with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. A residue is obtained, which is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 1.45 g of the expected product are thus isolated.

Mp=115-118° C.

¹H NMR (CDCl₃), δ (ppm): 3.89 (m, 2H); 4 (m, 2H); 4.7 (m, 4H); 5.12 (s, 2H); 6.51 (dxd, 1H); 6.71 (d, 1H); 7.12 (d, 1H); 7.38 (m, 5H).

EXAMPLE VII 7-aminopyrazino[1,2-a]benzimidazole (Compound No. VII-g) VII-1 7-nitropyrazino[1,2-a]benzimidazole (Compound No. XXIII)

A mixture of 0.6 g (2.12 mmol) of 2-iodo-4-nitrochlorobenzene (XXI) (G. A. Olah, J. Org. Chem., 1993 (58), 3194-3195), 0.2 g (2.1 mmol) of 2-aminopyrazine (XXII), 2.8 g (8.5 mmol) of cesium carbonate, 0.15 g (0.25 mmol) of Xantphos® (9,9-dimethyl-4,5-bis-(diphenylphosphino)xanthene) and 30 mg (0.13 mmol) of palladium diacetate in 20 ml of dry toluene is heated at 120° C. for 12 hours. After this period of time, the mixture is concentrated under reduced pressure and then taken up in 350 ml of dichloromethane and 200 ml of water. The organic phase is separated, washed with 100 ml of a saturated solution of sodium chloride, dried over magnesium sulphate, and then concentrated under reduced pressure. The resulting product is taken up in 10 ml of dichloromethane, and 0.23 g of the expected product is isolated in the form of a precipitate which is recovered by filtration. The filtrate is purified by silica column chromatography, elution being carried out with a mixture of ethyl acetate and heptane. A further 25 mg of product are thus isolated.

VII-2 7-aminopyrazino[1,2-a]benzimidazole (Compound No. VII-g)

A suspension of 0.22 g (1.03 mmol) of 7-nitropyrazino-[1,2-a]benzimidazole, obtained in the preceding step, of 0.5 g of Raney nickel and of 0.1 ml of hydrazine monohydrate (2.05 mmol) in 100 ml of ethanol is stirred at 20° C. for 2 hours. The insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure. 0.16 g of expected product is thus obtained in the form of a beige solid.

Mp=249-253° C.

¹H NMR (DMSO D₆), δ (ppm): 5.27 (broad peak, NH₂); 6.72 (m, 2H); 7.71 (d, 1H); 7.89 (d, 1H); 8.73 (d, 1H); 8.89 (s, 1H).

EXAMPLES VIII 7-aminopyrimido[1,2-a]benzimidazole (Compound No. VII-h and 8-aminopyrimido[1,2-a]-benzimidazole (Compound No. VII-i) VIII-1 7-nitropyrimido[1,2-a]benzimidazole hydrochloride and 8-nitropyrimido[1,2-a]benzimidazole hydrochloride (Compounds No. XXVI)

A mixture of 2 g (11.2 mmol) of 2-amino-5-nitro-benzimidazole (J. Med. Chem., 1995, 38(20), 4098-4105) and of 3.6 ml (15 mmol) of 1,1,3,3-tetraethoxypropane in 50 ml of ethanol and 2 ml of concentrated hydrochloric acid is refluxed for 12 hours. 1.97 g of a beige precipitate is recovered by filtration and is dried under reduced pressure. A mixture of isomers is obtained, which is used as it is in the subsequent step.

VIII-2 7-aminopyrimido[1,2-a]benzimidazole (Compound No. VII-h)

4.5 g (19.95 mmol) of tin chloride dihydrate in 4 ml of water are added to a suspension, heated to 100° C., of 1 g (3.99 mmol) of the mixture of compounds (XXVI), prepared in the preceding step, in 8 ml of concentrated hydrochloric acid. The reaction mixture is heated for 3 hours and then cooled and the pH of the medium is adjusted to 8 by successive additions of a 30% aqueous ammonia solution. The mixture is extracted three times with 100 ml of dichloromethane. The organic phases are combined, dried over magnesium sulphate, concentrated under reduced pressure and then purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 7-aminopyrimido[1,2-a]benzimidazole is thus isolated in the form of an orange solid.

¹H NMR (DMSO D₆), δ (ppm): 5.21 (m, NH₂); 6.7 (d, 1H); 6.81 (s, 1H); 6.95 (m, 1H); 7.9 (d, 1H); 7.58 (m, 1H); 9.25 (dxd, 1H).

VIII-3 8-aminopyrimido[1,2-a]benzimidazole (Compound No. VII-i)

During the extraction described in Example VIII-2, insoluble material precipitates in the aqueous phase. This insoluble material is recovered by filtration over sintered glass, which makes it possible to isolate 0.13 g of an orange solid corresponding to Compound No. VII-i.

¹H NMR (DMSO D₆), δ (ppm): 5.21 (m, NH₂); 6.91 (m, 2H); 7.2 (d, 1H); 7.51 (d, 1H); 8.57 (m, 1H); 9.12 (dxd, 1H).

EXAMPLE IX 6-amino-2,3-dihydro-3-hydroxy-1H-pyrrolo[1,2-a]benzimidazole (Compound No. VII-j) and 6-amino-2,3-dihydro-2-hydroxy-1H-pyrrolo[1,2-a]benzimidazole hydrochloride (Compounds No. VII-k) IX-1 2-(3-hydroxypyrrolidin-1-yl)-5-nitroaniline

According to a process similar to that described in Example II-1, starting from 3 g (19.22 mmol) of 2-fluoro-5-nitroaniline and 1.76 ml (21.14 mmol) of 3-hydroxypyrrolidine, 2 g of expected compound are obtained in the form of a yellow solid.

IX-2 2,3-dihydro-3-hydroxy-6-nitro-1H-pyrrolo-[1,2-a]benzimidazole and 2,3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo[1,2-a]benzimidazole

According to a process similar to that described in Example II-2, starting from 2 g (7.7 mmol) of 2-(3-hydroxypyrrolidin-1-yl)-5-nitroaniline, obtained in the preceding step, 48 mg of a yellow solid corresponding to 2,3-dihydro-3-hydroxy-6-nitro-1H-pyrrolo[1,2-a]benzimidazole and 280 mg of a yellow solid corresponding to 2,3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo[1,2-a]benzimidazole are obtained after purification by silica column chromatography.

IX-3 6-amino-2,3-dihydro-3-hydroxy-1H-pyrrolo-[1,2-a]benzimidazole (Compound No. VII-j)

According to a process similar to that described in Example VII-2, starting from 0.13 g (0.56 mmol) of 2,3-dihydro-3-hydroxy-6-nitro-1H-pyrrolo[1,2-a]-benzimidazole, prepared in step IX-2, 0.1 g of the expected amine is isolated in the form of a brown solid (the reaction mixture is stirred for 2 days at 20° C. in this case).

¹H NMR (CDCl₃), δ (ppm): 2.61 (m, 1H); 2.92 (m, 1H); 3.94 (m, 1H); 4.18 (m, 1H); 5.29 (m, 1H); 6.61 (d, 1H); 6.98 (s, 1H); 7.05 (d, 1H).

IX-4 6-amino-2,3-dihydro-2-hydroxy-1H-pyrrolo[1,2-a]-benzimidazole hydrochloride (Compounds No. VII-k)

A mixture of 0.3 g (1.36 mmol) of the 2,3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo[1,2-a]benzimidazole obtained in step IX-2 and of 100 mg of palladium-on-charcoal at 10% in 15 ml of ethanol and 2 ml of 1N hydrochloric acid is stirred for 5 hours at 20° C. under 4 bar of hydrogen. After this period of time, the reaction mixture is filtered over a celite buffer, the filtrate is concentrated under reduced pressure, and 0.35 g of the expected product is obtained in the form of a solid.

¹H NMR (DMSO D₆), δ (ppm): 3.05 (m, 1H); 3.55 (dxd, 1H); 4.15 (m, 1H); 4.45 (dxd, 1H); 5.1 (m, 1H); 7.0 (m, 1H); 7.3 (m, 1H); 7.66 (m, 1H).

EXAMPLE X 6-amino-2,3-dihydro-2-methoxy-1H-pyrrolo[1,2-a]benzimidazole (Compound No. VII-l) X-1 2,3-dihydro-2-methoxy-6-nitro-1H-pyrrolo-[1,2-a]benzimidazole

A solution of 0.28 g (1.28 mmol) of 2,3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo[1,2-a]benzimidazole (step IX-2 of Example IX) in 5 ml of tetrahydrofuran is added to a suspension, stirred under argon at 20° C., of 0.2 g (5 mmol) of sodium hydride at 60% in 10 ml of tetrahydrofuran. After stirring for fifteen minutes, 0.24 ml (2.5 mmol) of dimethyl sulphate is added. The reaction mixture is stirred at 20° C. for 12 hours and then poured in 100 ml of water and extracted three times with 50 ml of ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 70 mg of the expected product are thus isolated in the form of a foam.

X-2 6-amino-2,3-dihydro-2-methoxy-1H-pyrrolo-[1,2-a]benzimidazole (Compound No. VII-l)

According to a process similar to that described in Example VII-2, starting from 0.185 g (0.79 mmol) of 2,3-dihydro-2-methoxy-6-nitro-1H-pyrrolo[1,2-a]-benzimidazole, 60 mg of a beige solid corresponding to the expected product are obtained after purification by silica column chromatography.

Mp=140-142° C.

¹H NMR (CDCl₃), δ (ppm): 3.01 (dxd, 1H); 3.25 (dxd, 1H); 3.38 (s, 3H); 3.94 (dxd, 1H); 4.19 (dxd, 1H); 4.62 (m, 1H); 6.57 (dxd, 1H); 6.95 (d, 1H); 7.02 (d, 1H).

EXAMPLE XI 7-amino-4-methyl-1,2,3,4-tetrahydro-pyrimido[1,2-a]benzimidazole hydrochloride (1:1) (Compound No. VII-m) XI-1 N-(2-bromo-5-nitrophenyl)formimidoyl dichloride (XXVIII)

A solution of 5 g (20.4 mmol) of N-(2-bromo-5-nitrophenyl)formamide (XXVII) in 12 ml (164 mmol) of thionyl chloride and 4.5 ml (56 mmol) of sulphuryl chloride is heated at 60° C. for 24 hours. The reaction mixture is concentrated under reduced pressure and 5.3 g of a grey solid is obtained, which will be used as it is in the subsequent synthesis.

XI-2 N-(2-bromo-5-nitrophenyl)-N-(1-methyl-1H-3,4,5,6-tetrahydropyrimidin-2-ylidene)amine (XXX)

A suspension of 5.3 g (17.8 mmol) of the intermediate (XXVIII) in 30 ml of tetrahydrofuran is added, in several steps, to a solution, stirred at 0° C., of 10.5 ml (0.1 mol) of N-methyl-1,3-propanediamine (XXIX, n=3) in 50 ml of tetrahydrofuran. The reaction mixture is subsequently stirred at 20° C. for 48 hours and then poured into 200 ml of water. The mixture is extracted with three times 50 ml of ethyl acetate. The organic phases are combined, washed with 100 ml of a saturated aqueous solution of sodium chloride and then dried over sodium sulphate and concentrated under reduced pressure. The product obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 0.72 g of the expected product (XXIX) is thus isolated in the form of a yellow solid.

XI-3 4-methyl-7-nitro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (XXXI)

A mixture of 0.72 g (2.3 mmol) of intermediate (XXX), 0.16 g (0.28 mmol) of Xantphos® (9,9-dimethyl-4,5-bis-(diphenylphosphino)xanthene), 1.5 g (4.6 mmol) of cesium carbonate and 30 mg (0.14 mmol) of palladium diacetate in 20 ml of toluene is heated at 120° C. for 24 hours. After this period of time, the mixture is concentrated under reduced pressure and then purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 0.44 g of the expected product (XXXI) is thus isolated.

Mp=172-178° C.

¹H NMR (CDCl₃), δ (ppm): 2.42 (quint., 2H); 3.39 (s, 3H); 3.58 (t, 2H); 4.15 (t, 2H); 7.09 (d, 1H); 8.09 (dxd, 1H); 8.38 (d, 1H).

XI-4 7-amino-4-methyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole hydrochloride (1:1) (Compound No. VII-m)

0.2 ml (3.8 mmol) of hydrazine monohydrate is added to a suspension of 0.44 g (1.89 mmol) of compound (XXX) and 0.3 g of Raney nickel. The mixture is stirred at 20° C. for 3 hours and then filtered over a celite buffer, concentrated under reduced pressure and purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 0.36 g of the expected product (VII-m) is thus isolated. The compound can optionally be isolated in the form of a hydrochloride by taking up the product obtained in 50 ml of a 0.1N solution of hydrochloric acid in isopropanol and concentrating the solution obtained under reduced pressure. The hydrochloride of the amine (VII-m) is thus isolated.

Mp (HCl 1:1): 335-340° C.

¹H NMR (CDCl₃), δ (ppm): 2.17 (quint., 2H); 3.1 (s, 3H); 3.25 (t, 2H); 3.82 (t, 2H); 6.31 (dxd, 1H); 6.7 (d, 1H); 6.76 (d, 1H).

EXAMPLE XII 8-amino-5-methyl-1,2,3,4-tetrahydro-5-H-[1,3]diazepino[1,2-a]benzimidazole (Compound No. VII-n)

The compound (VII-n) is prepared according to a process similar to that described in Example (XIII), using the intermediates (XXVIII) and (XXIX, n=4).

Mp (2HCl): 330-336° C.

¹H NMR (CDCl₃), δ (ppm): 1.84 (m, 4H); 3.06 (s, 3H); 3.08 (m, 2H); 3.8 (m, 2H); 6.42 (dxd, 1H); 6.81 (d, 1H); 6.85 (s, 1H).

The following examples describe the preparation of certain compounds in accordance with the invention. These examples are not limiting and merely illustrate the present invention. The numbers of the compounds exemplified refer to those in Tables 2, 3 and 4. The elemental microanalyses, the LC-MS (liquid chromatography-mass spectrometry) analyses and the IR or NMR spectra confirm the structures of the compounds obtained.

EXAMPLE 1 Compound No. 1 of Table 2 N-(1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-7-yl)-5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxamide 1.1. ethyl 5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylate

A solution of 5.5 g (21.72 mmol) of 1,1′-azodicarbonyl-dipiperidine, in solution in 15 ml of dry toluene, is added, under argon at 20° C., dropwise, to a solution of 3 g (14.48 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 2.37 g (21.72 mmol) of 4-pyridylcarbinol and 5.45 ml (21.72 mmol) of n-tributylphosphine in 200 ml of toluene. The mixture is stirred at 20° C. for 48 h. The reaction mixture is subsequently concentrated under reduced pressure. The residue is purified by silica column chromatography (eluent: heptane/ethyl acetate). 3.2 g of the expected product are thus isolated, which product is used as it is in the subsequent synthesis.

1.2 N-(1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-7-yl)-5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxamide (Compound No. 1)

1.26 ml of trimethylaluminum (2M in toluene) are added, under argon, to a solution of 0.376 g (2.01 mmol) of 7-amino-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole (Saunders et al., J. Chem. Soc., 1955, 3275-3287) in 70 ml of dry toluene. After stirring at 0° C. for 15 min, the mixture is brought to 50° C. and the stirring is maintained for 30 min. The mixture is subsequently cooled to 0° C. 0.5 g (1.68 mmol) of ethyl 5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylate, obtained in step 1.1, is added. The reaction mixture is brought to reflux for 12 h, then cooled and added to 20 ml of an ice-cold 1N solution of hydrochloric acid. The pH of the aqueous phase is adjusted to 9. Insoluble material, recovered by filtration, is purified by silica column chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from a mixture of dichloromethane and heptane. 0.41 g of a white solid is obtained after drying under reduced pressure.

Melting point (base): 292-293° C.

¹H NMR (DMSO D₆), δ (ppm): 1.91 (m, 4H); 2.89 (t, 2H); 4.02 (t, 2H); 5.9 (s, 2H); 6.93 (d, 2H); 7.09 (txd, 1H); 7.5 (m, 5H); 7.89 (d, 1H); 8.4 (d, 2H); 10.35 (s, 1H).

EXAMPLE 2 Compound No. 2 of Table 2 N-(1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 2.1 ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate

A suspension of 1.035 g (5 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 0.865 g (6 mmol) of 3-fluorobenzyl chloride and 1.38 g (10 mmol) of potassium carbonate in 50 ml of dimethylformamide is stirred for 24 h at 60° C. The reaction mixture is subsequently cooled and poured into a mixture of ice-cold water and of ethyl acetate. After separation by settling out, the organic phase is separated and is then washed with twice 200 ml of water then with 200 ml of a saturated solution of sodium chloride. The solution is dried over magnesium sulphate and filtered and the filtrate is then concentrated under reduced pressure. 0.97 g of an oil is obtained, which oil is used as it is in the subsequent step.

2.2 N-(1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (Compound No. 2)

1.43 ml of trimethylaluminum (2M in toluene) are added, under argon, to a solution of 0.426 g (2.28 mmol) of 7-amino-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole (Saunders et al., J. Chem. Soc., 1955, 3275-3287) in 70 ml of dry toluene. After stirring at 0° C. for 15 min, the mixture is brought to 50° C. and the stirring is maintained for 30 min. The mixture is subsequently cooled to 0° C. and 0.6 g (1.9 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate, obtained in step 2.1, is added. The reaction mixture is brought to reflux for 12 h, then cooled and added to 20 ml of an ice-cold 1N solution of hydrochloric acid. The pH of the aqueous phase is adjusted to pH 9. An insoluble material is recovered by filtration and is purified by silica column chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from methanol. 0.46 g of a white solid is obtained after drying under reduced pressure.

Melting point (base): 286-287° C.

¹H NMR (DMSO D₆), δ (ppm): 2 (m, 4H); 2.9 (t, 2H); 4.05 (t, 2H); 5.88 (s, 2H); 7.11 (m, 10H); 7.91 (s, 1H); 10.38 (s, 1H).

EXAMPLE 3 Compound No. 3 of Table 2 N-(1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-7-yl)-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide 3.1 ethyl 1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

2 g (10 mmol) of ethyl pyrrolo[2,3-b]pyridine-2-carboxylate (WO2004101563) are added, portionwise, to a suspension of 0.44 g (11 mmol) of sodium hydride in 50 ml of DMF, stirred at 20° C. After stirring at ambient temperature for 1 h, 2.1 g (12 mmol) of benzyl bromide are added, dropwise, and the reaction mixture is stirred at ambient temperature for 20 h. 150 ml of water and 150 ml of ethyl ether are subsequently added with stirring. The aqueous phase is separated and extracted twice with 50 ml of ethyl ether. The organic phases are combined, washed with 100 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The resulting product is purified by silica column chromatography, elution being carried out with a mixture of heptane and dichloromethane. 2.3 g of the expected product are thus isolated.

Melting point=71-72° C.

3.2 N-(1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-7-yl)-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound No. 3)

1.1 ml of trimethylaluminum (2M in toluene) are added, under argon, to a solution of 0.32 g (1.71 mmol) of 7-amino-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole (Saunders et al., J. Chem. Soc., 1955, 3275-3287) in 20 ml of dry toluene. After stirring at 0° C. for 15 min, the mixture is brought to 50° C. and the stirring is maintained for 30 min. The mixture is subsequently cooled to 0° C. and 0.4 g (1.43 mmol) of ethyl 1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, obtained in step 3.1, is added. The reaction mixture is brought to reflux for 6 h and then cooled and 150 ml of water, 2 drops of a 35% aqueous solution of sodium hydroxide and 150 ml of dichloromethane are added with stirring. The aqueous phase is separated and extracted twice with 50 ml of dichloromethane. The organic phases are combined, washed with 100 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The resulting product is purified by silica column chromatography, elution being carried out with a mixture of methanol-dichloromethane. 0.55 g of product is thus isolated, which product is recrystallized from ethanol so as to obtain, after drying under vacuum, 0.45 g of the expected compound in the form of a powder.

Melting point=233-235° C.

¹H NMR (DMSO D₆), δ (ppm): 1.91 (m, 4H); 2.91 (t, 2H); 4.02 (t, 2H); 5.9 (s, 2H); 7.12 (m, 6H); 7.38 (m, 2H); 7.48 (m, 1H); 7.9 (s, 1H); 8.18 (dxd, 1H); 8.4 (dxd, 1H).

EXAMPLE 4 Compound No. 4 of Table 2 N-(1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-7-yl)-1-benzyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide 4.1 ethyl 1-benzyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

0.58 g (5.23 mmol) of benzyl alcohol, 1.4 g (5.23 mmol) of triphenylphosphine and 0.94 g (5.23 mmol) of diethyl azodicarboxylate (DEAD) are added, with stirring, to a suspension of 0.9 g (3.5 mmol) of ethyl 5-trifluoro-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

(Nazare, M. et al., Angewandte Chemie, International Ed., 2004, 43(34), 4526-4528) in 45 ml of dry tetrahydrofuran. After stirring at ambient temperature for 20 h, the reaction mixture is concentrated under reduced pressure and the resulting product is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and heptane. 1 g of the expected product is thus obtained.

Melting point=72-73° C.

4.2 N-(1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-7-yl)-1-benzyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound No. 4)

0.65 ml of trimethylaluminum (2M in toluene) is added, under argon, to a solution of 0.19 g (1.03 mmol) of 7-amino-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole (Saunders et al., J. Chem. Soc., 1955, 3275-3287) in 20 ml of dry toluene. After stirring at 0° C. for 15 min, the mixture is brought to 50° C. and the stirring is maintained for 30 min. The mixture is subsequently cooled to 0° C. and 0.3 g (0.86 mmol) of ethyl 1-benzyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, obtained in step 4.1, is added. The reaction mixture is brought to reflux for 6 h and then cooled and 150 ml of water, 2 drops of a 35% aqueous solution of sodium hydroxide and 150 ml of dichloromethane are added with stirring. The aqueous phase is separated and extracted twice with 50 ml of dichloromethane. The organic phases are combined, washed with 100 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The resulting product is purified by silica column chromatography, elution being carried out with a mixture of methanol-dichloromethane. 0.4 g of product is thus isolated, which product is recrystallized from acetonitrile so as to obtain, after drying under vacuum, 0.35 g of the expected compound in the form of a powder.

Melting point=241-243° C.

¹H NMR (DMSO D₆), δ (ppm): 1.91 (m, 4H); 2.93 (t, 2H); 4.05 (t, 2H); 5.98 (s, 2H); 7.15 (m, 5H); 7.42 (m, 3H); 7.9 (d, 1H), 8.7 (dxd, 2H), 10.5 (s, 1H).

EXAMPLE 5 Compound No. 5 of Table 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxamide

1.26 ml of trimethylaluminum (2M in toluene) are added, under argon, to a solution of 0.35 g (2.01 mmol) of 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259) in 70 ml of dry toluene. After stirring at 0° C. for 15 min, the mixture is brought to 50° C. and the stirring is maintained for 30 min. The mixture is cooled to 0° C. and 0.5 g (1.68 mmol) of ethyl 5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylate, obtained in step 1.1, is added. The reaction mixture is brought to reflux for 12 h and then cooled and poured into 20 ml of an ice-cold 1N solution of hydrochloric acid. The pH of the aqueous phase is adjusted to 9. An insoluble material is recovered by filtration and is purified by silica column chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from a mixture of dichloromethane-heptane. 0.23 g of a white solid is obtained after drying under reduced pressure.

Melting point (base): 266-267° C.

¹H NMR (DMSO D₆), δ (ppm): 2.6 (m, 2H); 2.9 (t, 2H); 4.08 (t, 2H); 5.9 (s, 2H); 6.95 (d, 2H); 7.1 (txd, 1H); 7.45 (m, 5H); 7.92 (d, 1H); 8.42 (d, 2H); 10.31 (s, 1H).

EXAMPLE 6 Compound No. 6 of Table 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

1.43 ml of trimethylaluminum (2M in toluene) are added, under argon, to a solution of 0.39 g (2.28 mmol) of 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259) in 70 ml of dry toluene. After stirring at 0° C. for 15 min, the mixture is brought to 50° C. and the stirring is maintained for 30 min. The mixture is subsequently cooled to 0° C. and 0.6 g (1.9 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate, obtained in step 2.1, is added. The reaction mixture is brought to reflux for 12 h and is then cooled and poured into 20 ml of an ice-cold 1N solution of hydrochloric acid. The pH of the aqueous phase is adjusted to 9. An insoluble material is recovered by filtration and is purified by silica column chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from a mixture of dichloromethane and heptane. 0.45 g of a white solid is obtained after drying under reduced pressure.

Melting point (base): 256-257° C.

¹H NMR (DMSO D₆), δ (ppm): 2.56 (m, 2H); 2.91 (t, 2H); 4.04 (t, 2H); 5.9 (s, 2H); 7.2 (m, 10H); 7.92 (d, 1H); 10.32 (s, 1H).

EXAMPLE 7 Compound No. 7 of Table 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

0.67 ml of trimethylaluminum (2M in toluene) is added, under argon, to a solution of 0.185 g (1.07 mmol) of 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259) in 20 ml of dry toluene. After stirring at 0° C. for 15 min, the mixture is brought to 50° C. and the stirring is maintained for 30 min. The mixture is subsequently cooled to 0° C. and 0.25 g (0.89 mmol) of ethyl 1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, obtained in step 3.1, is added. The reaction mixture is brought to reflux for 6 h and then cooled and 150 ml of water, 2 drops of a 35% aqueous solution of sodium hydroxide and 150 ml of dichloromethane are added with stirring. The aqueous phase is separated and extracted twice with 50 ml of dichloromethane. The organic phases are combined, washed with 100 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The resulting product is purified by silica column chromatography, elution being carried out with a mixture of methanol and dichloromethane. 0.34 g of product is thus isolated, which product is recrystallized from ethanol so as to obtain, after drying under vacuum, 0.31 g of the expected compound in the form of a powder.

Melting point=251-252° C.

¹H NMR (DMSO D₆), δ (ppm): 2.6 (m, 2H); 2.9 (t, 2H); 4.04 (t, 2H); 5.9 (s, 2H); 7.15 (m, 9H); 7.9 (d, 1H); 8.18 (dxd, 1H); 8.4 (dxd, 1H).

EXAMPLE 8 Compound No. 8 of Table 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-benzyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

0.65 ml of trimethylaluminum (2M in toluene) is added, under argon, to a solution of 0.18 g (1.03 mmol) of 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259) in 20 ml of dry toluene. After stirring at 0° C. for 15 min, the mixture is brought to 50° C. and the stirring is maintained for 30 min. The mixture is subsequently cooled to 0° C. and 0.3 g (0.86 mmol) of ethyl 1-benzyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, obtained in step 4.1, is added. The reaction mixture is brought to reflux for 6 h and then cooled and 150 ml of water, 2 drops of a 35% aqueous solution of sodium hydroxide and 150 ml of dichloromethane are added with stirring. The aqueous phase is separated and extracted twice with 50 ml of dichloromethane. The organic phases are combined, washed with 100 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The resulting product is purified by silica column chromatography, elution being carried out with a mixture of methanol-dichloromethane. 0.37 g of product is thus isolated, which product is recrystallized from acetonitrile so as to obtain, after drying under vacuum, 0.3 g of the expected compound in the form of a powder. Melting point=268-270° C.

¹H NMR (DMSO D₆), δ (ppm): 2.6 (m, 2H); 2.9 (t, 2H); 4.04 (t, 2H); 6 (s, 2H); 7.12 (m, 5H); 7.42 (m, 3H); 7.92 (s, 1H); 8.7 (d, 2H).

EXAMPLE 9 Compound No. 148 of Table 3 N-(pyrido[1,2-a]benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

1.19 ml of trimethylaluminum (2M in toluene) are added, under argon, to a solution of 0.348 g (1.9 mmol) of 7-aminopyrido[1,2-a]benzimidazole (Begunov et al., Russian J. Org. Chem., 2004, (40), 11, 1694-1696) in 70 ml of dry toluene. After stirring at 0° C. for 15 min, the mixture is brought to 50° C. and the stirring is maintained for 30 min. The mixture is subsequently cooled to 0° C. and 0.5 g (1.9 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate, obtained in step 2.1, is added. The reaction mixture is brought to reflux for 12 h and then cooled and added to 20 ml of an ice-cold 1N solution of hydrochloric acid. The pH of the aqueous phase is adjusted to 9. An insoluble material is recovered by filtration and purified by preparative chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from methanol. 0.53 g of the expected product is obtained in the form of a white solid after drying under reduced pressure.

Melting point (base): 261-262° C.

¹H NMR (DMSO D₆), δ (ppm): 5.9 (s, 2H); 7.01 (m, 6H); 7.55 (m, 6H); 8.2 (d, 2H); 9.0 (s, 1H).

EXAMPLE 10 Compound No. 149 of Table 3 N-(pyrido[1,2-a]benzimidazol-7-yl)-5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxamide

1.51 ml of trimethylaluminum (2M in toluene) are added, under argon, to a solution of 0.442 g (2.41 mmol) of 7-aminopyrido[1,2-a]benzimidazole (Begunov et al., Russian J. Org. Chem., 2004, (40), 11, 1694-1696) in 70 ml of dry toluene. After stirring at 0° C. for 15 min, the mixture is brought to 50° C. and the stirring is maintained for 30 min. The mixture is subsequently cooled to 0° C. and 0.6 g (2.01 mmol) of ethyl 5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylate, obtained in step 1.1, is added. The reaction mixture is brought to reflux for 12 h and then cooled and added to 20 ml of an ice-cold 1N solution of hydrochloric acid. The pH of the aqueous phase is adjusted to 9. An insoluble material is filtered off and purified by preparative chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from methanol. 0.35 g of the expected product is obtained in the form of a white solid after drying under reduced pressure.

Melting point (base): 277-278° C.

¹H NMR (DMSO D₆), δ (ppm): 5.9 (s, 2H); 6.99 (m, 3H); 7.11 (dxt, 1H); 7.58 (m, 6H); 8.21 (m, 2H); 8.44 (d, 2H); 9.05 (d, 1H).

EXAMPLE 11 Compound No. 150 of Table 3 N-(pyrimido[1,2-a]benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 11.1 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid

An aqueous solution of sodium hydroxide, prepared from 1.15 g (28.92 mmol) of sodium hydroxide pellets in 50 ml of water, is added to a solution of 7.6 g (24.10 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (obtained in step 2.1) in 240 ml of ethanol. The mixture is heated for two hours and then concentrated under reduced pressure. The resulting solid is taken up in 200 ml of water. The solution is washed with twice 100 ml of ethyl ether, acidified by successive additions of small amounts of concentrated hydrochloric acid and then extracted with 200 ml of ethyl acetate. The organic phase is finally washed twice with 100 ml of water and once with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. After drying at 50° C. under reduced pressure, 6.4 g of the expected product are obtained in the form of a solid that will be used as it is in the subsequent step.

11.2 N-(pyrimido[1,2-a]benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (Compound No. 150)

140 mg (0.532 mmol) of 70% pure 7-aminopyrimido[1,2-a]-benzimidazole (VII-h) are added to a solution, stirred at 20° C., of 0.22 g (0.76 mmol) of compound prepared in step 11.1, 146 mg (0.76 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 103 mg (0.76 mmol) of 1-hydroxybenzotriazole (HOBT) in 5 ml of DMF. The reaction mixture is stirred at 20° C. for 48 hours and is then poured into 50 ml of water. The mixture is subsequently extracted with 3 times 30 ml of ethyl acetate. The combined organic phases are washed twice with 20 ml of water, dried over magnesium sulphate and then concentrated under reduced pressure. The product obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 90 mg of the expected product are thus isolated.

Mf=295-298° C.

¹H NMR (DMSO D₆), δ (ppm): 10.7 (s, 1H); 9.49 (d, 1H); 8.82 (d, 1H); 8.3 (m, 2H); 7.79 (d, 1H); 7.6 (m, 2H); 7.47 (s, 1H); 7.31 (m, 1H); 7.17 (m, 2H); 7.05 (m, 1H); 6.82 (m, 2H); 5.93 (s, 2H).

EXAMPLE 12 Compound No. 154 of Table 4 N-(2-methoxypyrrolo[1,2-a]benzimidazol-6-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide hydrochloride (1:1)

Compound 154 is prepared, according to a process similar to the method described in Example 11.2, from the acid prepared in step 11.1 and 6-amino-2-methoxypyrrolo[1,2-a]benzimidazole (VII-l). The resulting solid is subsequently dissolved under hot conditions in a mixture of 2.1 ml of 0.1N hydrochloric acid in isopropanol and 1 ml of methanol. After cooling of the medium, a precipitate is recovered by filtration and is dried under reduced pressure. The expected product is thus isolated in the form of a hydrochloride.

Mp (HCl 1:1)=220-225° C.

¹H NMR (DMSO D₆), δ (ppm): 3.21 (d, 1H); 3.35 (s, 3H); 3.52 (dxd, 1H); 4.38 (m, 2H); 4.8 (m, 1H); 5.89 (s, 2H); 6.89 (m, 2H); 6.91-7.33 (m, 3H); 7.4-7.8 (m, 4H); 8.27 (s, 1H); 10.68 (s, 1H).

EXAMPLE 13 No. 151 of Table 3 N-(pyrazino[1,2-a]benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide hydrochloride (1:1)

Compound 151 is prepared, according to a process similar to the method described in Example 12, from the acid prepared in step 11.1 and 7-aminopyrazino[1,2-a]-benzimidazole (VII-g).

Mp (HCl 1:1)=225-230° C.

¹H NMR (DMSO D₆), δ (ppm): 5.91 (s, 2H); 6.81-7.38 (m, 5H); 7.58 (m, 3H); 7.91 (d, 1H); 8.22 (d, 1H); 8.49 (m, 2H); 9.2 (d, 1H); 9.33 (s, 1H); 10.8 (s, 1H).

EXAMPLE 14 No. 26 of Table 2 N-(2,3-dihydro-3-methylimidazo[1,2-a]benzimidazol-6-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

Compound 26 is prepared, according to a process similar to the method described in Example 1.2, from ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate, obtained in step 2.1, and 6-amino-2,3-dihydro-1-methyl-imidazo[1,2-a]benzimidazole (VII-c).

Mp=281-282° C.

¹H NMR (DMSO D₆), δ (ppm): 3.1 (s, 3H); 4.1-4.35 (m, 4H); 5.89 (s, 2H); 6.82 (m, 2H); 6.92-7.2 (m, 2H); 7.21-7.35 (m, 2H); 7.39 (s, 1H); 7.53 (m, 3H); 7.91 (s, 1H).

EXAMPLE 15 No. 50 of Table 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-[(quinolin-2-yl)methyl]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide 15.1 ethyl 1-[(quinolin-2-yl)methyl]-5-trifluoro-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

0.14 g (0.871 mmol) of (quinolin-2-yl)methanol, 0.228 g (0.871 mmol) of triphenylphosphine and 0.151 g (0.871 mmol) of diethyl azodicarboxylate (DEAD) are added, with stirring, to a suspension of 0.15 g (0.581 mmol) of ethyl 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Nazare, M. et al., Angewandte Chemie, International Ed., 2004, 43(34), 4526-4528) in 2 ml of dry tetrahydrofuran. After stirring at ambient temperature for 20 h, the reaction mixture is concentrated under reduced pressure and the resulting product is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and heptane. 0.18 g of the expected product is thus obtained in the form of a yellow oil.

15.2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-[(quinolin-2-yl)methyl]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound No. 50)

Compound 50 is prepared, according to a process similar to the method described in Example 5, from 0.18 g (0.45 mmol) of compound obtained in step 15.1 and 0.094 g (0.541 mmol) of 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259). 0.22 g of the expected product is thus obtained.

Mp=300-301° C.

¹H NMR (DMSO D₆), δ (ppm): 2.61 (q, 2H); 2.94 (t, 2H); 4.08 (t, 2H); 6.26 (s, 2H); 7.22 (d, 1H); 7.37 (d, 1H); 7.55-7.46 (m, 2H); 7.6 (s, 1H); 7.67 (dxt, 1H); 7.8 (d, 1H); 7.95-7.81 (m, 2H); 8.27 (d, 1H); 8.73 (s, 2H); 10.65 (s, 1H).

EXAMPLE 16 No. 25 of Table 2 N-(1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 16.1 N-(2-benzyloxycarbonyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

The compound is prepared, according to a process similar to that described in Example 11.2, from the 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid described in Example 11.1 and the amine VII-f.

16.2 N-(1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (Compound No. 25)

A suspension of 1 g (1.69 mmol) of the compound prepared in the preceding step and of 0.1 g of palladium-on-charcoal at 10% in 100 ml of ethanol is stirred at 20° C. for 6 hours under 5.5 bar of hydrogen. The suspension is subsequently filtered over a celite buffer and concentrated under reduced pressure. The resulting product is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. The purified product is taken up in 10 ml of a 0.1N solution of hydrochloric acid in isopropanol, the solution is concentrated under reduced pressure and the resulting solid is triturated from ethyl ether so as to make it possible to isolate 0.48 g of the expected product.

Mp (1HCl)=276-284° C.

¹H NMR (DMSO D₆), δ (ppm): 3.73 (t, 2H); 4.38 (t, 2H); 4.59 (s, 3H); 5.59 (s, 2H); 6.9 (m, 2H); 7.02 (txd, 1H); 7.15 (txd, 1H); 7.31 (m, 1H); 7.45 (s, 1H); 7.58 (m, 3H); 8.1 (s, 1H); 9.97 (s, 1H); 10.45 (s, 1H).

EXAMPLE 17 No. 81 of Table 2 N-(3-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]-benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

Compound 81 is prepared according to a process similar to that described in Example 6, from ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate obtained in step 2.1 and 7-amino-3-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole (VII-e).

¹H NMR (DMSO D₆), δ (ppm): 2.45 (s, 3H); 2.89 (t, 2H); 3.74 (s, 2H); 4.1 (t, 2H); 5.9 (s, 2H); 6.81-7.6 (m, 10H); 7.97 (d, 1H); 10.46 (s, 1H).

EXAMPLE 18 No. 84 of Table 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-5-fluoro-1-(2-benzyloxyethyl)-1H-indole-2-carboxamide 18.1 ethyl 5-fluoro-1-(2-benzyloxyethyl)-1H-indole-2-carboxylate

94 μl (0.657 mmol) of 2-benzyloxyethanol and 50.4 mg (0.438 mmol) of (cyanomethylene)trimethylphosphorane (Tet. Lett., 1996, 37, 2459-2462) are added to a solution of 68 mg (0.329 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate in 2 ml of toluene, stirred at 20° C. The reaction mixture is heated at 110° C. for 12 hours and then concentrated under reduced pressure, taken up in 20 ml of ethyl ether, filtered over a celite buffer and concentrated under reduced pressure. The residue obtained is purified by preparative HPLC, elution being carried out with a mixture of water, acetonitrile and trifluoroacetic acid. 99 mg of a yellow oil are thus isolated.

¹H NMR (DMSO D₆), δ (ppm): 1.3 (t, 3H); 3.72 (t, 2H); 4.28 (q, 2H); 4.38 (s, 2H); 4.81 (t, 2H); 7.28-7.07 (m, 7H); 7.45 (dxd, 1H); 7.68 (dxd, 1H).

18.2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-5-fluoro-1-(2-benzyloxyethyl)-1H-indole-2-carboxamide (Compound No. 84)

Compound 84 is prepared, according to a process similar to the method described in Example 6, from ethyl 5-fluoro-1-(2-benzyloxyethyl)-1H-indole-2-carboxylate, obtained in the preceding step, and 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259).

Mp=186-187° C.

¹H NMR (DMSO D₆), δ (ppm): 2.63 (m, 2H); 2.93 (m, 2H); 3.75 (m, 2H); 4.09 (m, 2H); 4.39 (s, 2H); 4.81 (m, 2H); 7.01-7.19 (m, 6H); 7.25 (s, 1H); 7.31-7.62 (m, 3H); 7.62 (dxd, 1H); 7.97 (m, 1H); 10.23 (s, 1H).

EXAMPLE 19 No. 82 of Table 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-5-fluoro-1-{2-[(5-methylpyridin-2-yl)oxy]ethyl}-1H-indole-2-carboxamide 19.1 2-[(5-methylpyridin-2-yl)oxy]ethanol

A suspension of 0.291 ml (4.12 mmol) of 2-bromoethanol, of 0.3 g (2.75 mmol) of 2-hydroxy-5-methylpyridine and of 0.85 g (6.18 mmol) of potassium carbonate in 3 ml of dimethylformamide is vigorously stirred for 12 hours at reflux. The mixture is subsequently diluted with 100 ml of water and extracted with 100 ml of dichloromethane. The organic phase is washed with 50 ml of water, dried over sodium sulphate, concentrated under reduced pressure and then chromatographed on a silica column, elution being carried out with a mixture of hexane and ethyl acetate. The expected product is thus isolated.

¹H NMR (DMSO D₆), δ (ppm): 2.2 (s, 3H); 3.66-3.71 (m, 2H); 4.22 (t, 2H); 4.77 (t, 1H); 6.71 (d, 1H); 7.51 (dxd, 1H); 7.95 (dxd, 1H).

19.2 ethyl 5-fluoro-1-{2-[(5-methylpyridin-2-yl)-oxy]ethyl}-1H-indole-2-carboxylate

The ethyl 5-fluoro-1-[2-[(5-methylpyridin-2-yl)oxy]-ethyl]-1H-indole-2-carboxylate intermediate is prepared in a manner similar to the method described in Example 18.1, from ethyl 5-fluoro-1H-indole-2-carboxylate and 2-(5-methylpyridin-2-yloxy)ethanol prepared in the preceding step.

19.3 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-5-fluoro-1-{2-[(5-methylpyridin-2-yl)oxy]ethyl}-1H-indole-2-carboxamide (Compound No. 82)

Compound 82 is prepared according to a process similar to the method described in Example 6, from the compound obtained in the preceding step, and 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259).

Mp=209-210° C.

¹H NMR (DMSO D₆), δ (ppm): 2.11 (s, 3H); 2.61 (m, 2H); 2.91 (m, 2H); 4.09 (m, 2H); 4.49 (m, 2H); 4.91 (m, 2H); 6.41 (d, 1H); 7.11 (dxt, 1H); 7.21 (s, 1H); 7.32-7.56 (m, 4H); 7.62 (dxd, 1H); 7.89 (d, 1H); 7.97 (d, 1H); 10.29 (s, 1H).

EXAMPLE 20 No. 83 of Table 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-5-fluoro-1-[2-{[(5-trifluoromethyl)pyridin-2-yl]oxy}ethyl]-1H-indole-2-carboxamide 20.1 2-[(5-trifluoromethyl)pyridin-2-yl)oxy]ethanol

The compound is prepared according to a method similar to that described in Example 19.1, from 2-bromoethanol and 2-hydroxy-5-(trifluoromethyl)pyridine.

20.2 ethyl 5-fluoro-1-[2-{[(5-trifluoromethyl)pyridin-2-yl]oxy}ethyl]-1H-indole-2-carboxylate

This intermediate is prepared, in a manner similar to the method described in Example 18.1, from ethyl 5-fluoro-1H-indole-2-carboxylate and 2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]ethanol prepared in the preceding step.

20.3 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-5-fluoro-1-[2-{[(5-trifluoromethyl)pyridin-2-yl]oxy}-ethyl]-1H-indole-2-carboxamide (Compound No. 83)

Compound 83 is prepared, according to a process similar to the method described in Example 6, from ethyl 5-fluoro-1-[2-[[(5-trifluoromethyl)pyridin-2-yl]oxy]-ethyl]-1H-indole-2-carboxylate, obtained in the preceding step, and 6-amino-2,3-dihydro-1H-pyrrolo-[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259).

[MH]⁺=524

¹H NMR (DMSO D₆), δ (ppm): 2.61 (m, 2H); 2.89 (m, 2H); 4.05 (m, 2H); 4.59 (m, 2H); 4.98 (m, 2H); 6.69 (d, 1H); 7.11 (dxt, 1H); 7.23 (s, 1H); 7.3-7.52 (m, 3H); 7.63 (dxd, 1H); 7.84 (dxd, 1H); 7.97 (s, 1H); 8.45 (s, 1H); 10.28 (s, 1H).

EXAMPLE 21 No. 127 of Table 2 N-(3,4-dihydro-1H-oxazino[1,4][4,3-a]benzimidazol-7-yl)-1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide 21.1 2-amino-3-iodo-5-fluoropyridine

5 g (44.6 mmol) of 2-amino-5-fluoropyridine, 13.9 g (44.6 mmol) of silver sulphate and 400 ml of ethanol are introduced into a 500 ml two-necked flask equipped with a magnetic stirrer. 11.31 g (44.6 mmol) of powdered iodine are subsequently added in small portions. The stirring is continued at ambient temperature for 24 hours. The insoluble material is removed by filtration and washed with ethanol and the filtrate is concentrated under reduced pressure. The residue thus obtained is taken up in a mixture of ethyl acetate (200 ml) and of a solution of sodium carbonate (200 ml). After separation, the organic phase is washed successively with a 25% aqueous solution of sodium thiosulphate and then with a saturated aqueous solution of sodium chloride, and then dried over sodium sulphate and concentrated under reduced pressure. The resulting solid is purified by silica column chromatography, elution being carried out with a mixture of n-heptane and ethyl acetate. 2.67 g (11.22 mmol) of the expected product are obtained.

¹H NMR (DMSO D₆), δ (ppm): 7.95 (s, 1H); 7.85 (s, 1H); 5.9 (s, NH₂).

21.2 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

0.5 g (2.10 mmol) of 2-amino-3-iodo-5-fluoropyridine obtained in step 5.1, 0.55 g (6.3 mmol) of pyruvic acid, 0.71 g (6.3 mmol) of 1,4-diazabicyclo[2.2.2]octane (DABCO) and 15 ml of anhydrous dimethylformamide are introduced into a 25 ml sealed tube equipped with a magnetic stirrer and subjected to sparging with argon. After a few minutes, 0.05 g (0.22 mmol) of palladium acetate is added. The reaction mixture is kept stirring and subjected to sparging with argon for 20 minutes and then rapidly sealed and brought to 100° C. for 2 h 30. The cooled solution is concentrated under reduced pressure. The residue is subsequently taken up with ethyl acetate (100 ml) and water (75 ml). The organic phase is washed with water and then extracted with twice 50 ml of a 2N aqueous solution of sodium hydroxide. The basic aqueous phases are combined, cooled to 0° C. and then acidified by adding hydrochloric acid (pH 3). The medium is extracted with ethyl acetate (4×50 ml), and the combined organic phases are dried over sodium sulphate and then concentrated under reduced pressure. 0.158 g (0.88 mmol) of the expected product is obtained in the form of a yellow powder.

¹H NMR (DMSO D₆), δ (ppm): 13.2 (s, 1H); 12.4 (s, 1H); 8.4 (d, 1H); 7.95 (dd, 1H); 7.1 (d, 1H).

21.3 ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

0.2 g (1.11 mmol) of acid obtained in step 21.2 and 10 ml of ethanol are introduced into a 100 ml round-bottomed flask equipped with a magnetic stirrer. 1 ml of concentrated sulphuric acid is added to the reaction mixture, which is subsequently brought to reflux for 18 hours. The cooled solution is concentrated to dryness under reduced pressure. The residue is taken up with ethyl acetate (50 ml) and the product is washed successively with a normal aqueous solution of sodium hydroxide (2×10 ml), with water (10 ml) and then with a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulphate and then concentrated under reduced pressure. 0.21 g of the expected product is isolated.

¹H NMR (DMSO D₆), δ (ppm): 12.6 (s, NH); 8.4 (d, 1H); 8.0 (dd, 1H); 7.1 (d, 1H); 4.35 (q, 2H); 1.35 (t, 3H).

21.4 ethyl 1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]-pyridine-2-carboxylate

The ethyl 1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was prepared according to a method similar to that described in Example 4.1, from benzyl alcohol and the ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate prepared in the preceding step.

Mp=74-75° C.

21.5 N-(3,4-dihydro-1H-oxazino[1,4][4,3-a]-benzimidazol-7-yl)-1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]-pyridine-2-carboxamide (Compound No. 127)

Compound No. 127 is prepared, according to a method similar to that described in Example 4.2, from ethyl 1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, described in the preceding step, and 7-aminomorpholino[4,3-a]benzimidazole (Mullock, E. B., J. Chem. Soc. Section C, 1970, (6), 829-833).

Mp=231-232° C.

¹H NMR (DMSO D₆), δ (ppm): 4.15 (m, 4H); 4.91 (s, 2H); 5.9 (s, 2H); 7.02-7.26 (m, 5H); 7.35 (s, 1H); 7.5 (m, 2H); 8.01 (s, 1H); 8.12 (dxd, 1H); 8.46 (m, 1H); 10.44 (s, 1H).

EXAMPLE 22 Compound No. 128 of Table No. 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Compound No. 128 is prepared, according to a method similar to that described in Example 4.2, from ethyl 1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, described in Example 21.4, and 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259).

Mp=259-260° C.

¹H NMR (DMSO D₆), δ (ppm): 2.59 (m, 2H); 2.89 (t, 2H); 4.05 (t, 2H); 5.89 (s, 2H); 7.01-7.24 (m, 5H); 7.35 (m, 2H); 7.45 (dxd, 1H); 7.91 (s, 1H); 8.1 (dxd, 1H); 8.41 (m, 1H); 10.41 (s, 1H).

EXAMPLE 23 Compound No. 129 of Table No. 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-benzyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide 23.1 3-amino-2-iodo-6-(trifluoromethyl)pyridine

1.56 g (6.17 mmol) of iodine are added, portionwise, to a mixture, stirred under argon at 20° C., of 1 g (6.17 mmol) of 3-amino-6-(trifluoromethyl)pyridine and 1.25 g (6.17 mmol) of silver sulphate in 40 ml of ethanol. The stirring is maintained for 18 hours. The insoluble material is removed by filtration and is washed with ethanol, the filtrate is concentrated under reduced pressure, and the residue is taken up in 100 ml of dichloromethane. The organic phase is washed successively with 20 ml of a 5% aqueous solution of sodium hydroxide, 40 ml of water and 20 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulphate, concentrated under reduced pressure and then purified by silica column chromatography (eluents: heptane-ethyl acetate). 1.17 g of the expected product are thus isolated, which product is used as it is in the subsequent synthesis.

23.2 5-trifluoromethylpyrrolo[3,2-b]pyridine-2-carboxylic acid

0.5 g (1.74 mmol) of 3-amino-2-iodo-6-(trifluoro-methyl)pyridine, obtained in step 23.1, 0.45 g (5.21 mmol) of pyruvic acid, 0.51 ml (5.21 mmol) of 1,4-diazabicyclo[2.2.2]octane and 10 ml of dry dimethylformamide are introduced, under argon, into a sealed tube. The solution is degassed for a few minutes and then 0.19 g (0.87 mmol) of palladium acetate is added, the tube is sealed and the whole is brought to reflux at 130° C. for 4 hours. The cooled solution is subsequently concentrated under reduced pressure and the residue is taken up with 100 ml of ethyl acetate. The organic phase is extracted successively with twice 50 ml of a 2N aqueous solution of sodium hydroxide. The basic aqueous phases are combined, cooled to 0° C., acidified by adding hydrochloric acid, and then extracted with 4 times 50 ml of ethyl acetate. These organic phases are combined, washed with 20 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulphate and then concentrated under reduced pressure. 0.22 g of product is obtained, which product is used as it is in the subsequent step.

23.3 ethyl 5-(trifluoromethyl)pyrrolo[3,2-b]pyridine-2-carboxylate

1 ml (18.71 mmol) of concentrated sulphuric acid is added to a solution of 0.2 g (0.87 mmol) of 5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid, obtained in step 23.2, in 10 ml of ethanol. The solution is stirred at reflux for 20 hours and then cooled and concentrated under reduced pressure. The resultant residue is subsequently taken up with 50 ml of dichloromethane and then washed successively with 20 ml of a saturated aqueous solution of sodium hydrogen carbonate, 40 ml of water and 20 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulphate and then concentrated under reduced pressure. 0.19 g of product is obtained, which product is used as it is in the subsequent step.

23.4 ethyl 1-benzyl-5-trifluoromethylpyrrolo[3,2-b]-pyridine-2-carboxylate

Ethyl 1-benzyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]-pyridine-2-carboxylate was prepared, according to a method similar to that described in Example 4.1, from benzyl alcohol and the compound prepared in the preceding step.

23.5 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-benzyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (Compound No. 129)

Compound No. 129 is prepared, according to a method similar to that described in Example 4.2, from ethyl 1-benzyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate, described in the preceding step, and 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259).

Mp=251-252° C.

¹H NMR (DMSO D₆), δ (ppm): 2.61 (m, 2H); 2.91 (t, 2H); 4.09 (t, 2H); 5.92 (s, 2H); 7.05-7.29 (m, 5H); 7.31-7.5 (m, 2H); 7.56 (s, 1H); 7.7 (d, 1H); 7.91 (s, 1H); 8.29 (d, 1H); 10.51 (s, 1H).

EXAMPLE 24 Compound No. 130 of Table No. 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-[(pyridin-4-yl)methyl]-5-fluoro-1H-pyrrolo[2,3-b]-pyridine-2-carboxamide 24.1 ethyl 1-[(pyridin-4-yl)methyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

9.18 g (36.02 mmol) of 1,1′-(azodicarbonyl)dipiperidine are added, in a quarter of an hour, to a solution, stirred at 20° C., of 5 g (24.02 mmol) of ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Example 21.3), 3.97 g (36.02 mmol) of (pyridin-4-yl)methanol and 7.5 g (36.02 mmol) of tributylphosphine in 150 ml of toluene. The reaction mixture is stirred at 20° C. for 16 hours, filtered over a celite buffer, concentrated under reduced pressure and then taken up in 100 ml of dichloromethane. The organic solution is washed twice with 50 ml of a 5% aqueous solution of potassium carbonate and then once with 50 ml of water, dried over sodium sulphate and concentrated under reduced pressure. The product obtained is chromatographed on a silica column, elution being carried out with a mixture of heptane and ethyl acetate. 4.5 g of the expected ester are thus isolated.

Mp=120-121° C.

24.2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-[(pyridin-4-yl)methyl]-5-fluoro-1H-pyrrolo-[2,3-b]pyridine-2-carboxamide (Compound No. 130)

Compound No. 130 is prepared, according to a method similar to that described in Example 1.2, from ethyl 1-[(pyridin-4-yl)methyl]-5-fluoro-1H-pyrrolo[2,3-b]-pyridine-2-carboxylate, described in the preceding step, and 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259).

Mp=283-285° C.

¹H NMR (DMSO D₆), δ (ppm): 2.62 (m, 2H); 2.92 (t, 2H); 4.09 (t, 2H); 5.93 (s, 2H); 7.01 (d, 2H); 7.38 (d, 1H); 7.49 (m, 2H); 7.95 (s, 1H); 8.2 (d, 1H); 8.45 (m, 3H); 10.42 (s, 1H).

EXAMPLE 25 Compound No. 131 of Table No. 2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-[(pyridin-4-yl)methyl]-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

25.1 ethyl 1-[(pyridin-4-yl)methyl]-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

According to a process similar to that described in Example 24.1, using 5 g (18.4 mmol) of ethyl 5-tri-fluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (Example 23.3) and 3.04 g (27.6 mmol) of (pyridin-4-yl)methanol, 4.2 g of the expected compound are isolated. Mp=130-131° C.

25.2 N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)-1-[(pyridin-4-yl)methyl]-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (Compound No. 131)

According to a process similar to that described in Example 24.2, using 0.3 g (0.86 mmol) of compound obtained in the preceding step and 0.178 g (1.03 mmol) of 6-amino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (Freedman et al., J. Het. Chem., 1966, 3, (3), 257-259), 0.25 g of the expected compound is isolated in the form of a white solid.

Mp=270-271° C.

¹H NMR (DMSO D₆), δ (ppm): 2.61 (m, 2H); 2.92 (t, 2H); 4.09 (t, 2H); 5.99 (s, 2H); 7.01 (d, 2H); 7.43 (m, 2H); 7.71 (s, 1H); 7.79 (d, 1H); 7.95 (s, 1H); 8.25 (d, 1H); 8.43 (d, 2H); 10.51 (s, 1H).

EXAMPLE 26 Compound No. 132 of Table No. 2 N-(4-methyl-1,2,3,4-tetrahydropyrimido[1,2-a]-benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide hydrochloride (1:1)

Compound 132 is prepared, according to a process similar to that of Example 11.2, from 0.312 g (1.09 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid and 0.22 g (1.09 mmol) of 7-amino-4-methyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (VII-m). 0.41 g of the expected product is isolated in the form of a pale yellow solid. The compound is taken up in 50 ml of a 0.1N solution of hydrochloric acid in isopropanol. The solution obtained is concentrated under reduced pressure and compound 139 is thus isolated in the form of a hydrochloride.

Mp (HCl 1:1)=343-349° C.

¹H NMR (DMSO D₆), δ (ppm):

EXAMPLE 27 Compound No. 24 of Table No. 2 N-(3,4-dihydro-1H-oxazino[1,4][4,3-a]benzimidazol-7-yl)-1-benzyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Compound 24 was prepared, according to a method similar to that described in Example 4.2, by reaction between ethyl 1-benzyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]-pyridine-2-carboxylate, described in Example 4.1, and 7-aminooxazino[1,4][4,3-a]benzimidazole (Mullock, E. B., J. Chem. Soc. Section C, 1970, (6), 829-833).

Mp=236-237° C.

¹H NMR (DMSO D₆), δ (ppm): 4.12 (m, 4H); 4.91 (s, 2H); 5.95 (s, 2H); 7.02-7.28 (m, 5H); 7.5 (m, 3H); 8.01 (d, 1H); 8.68 (d, 1H); 8.78 (d, 1H); 10.55 (s, 1H).

EXAMPLE 28 Compound No. 15 of Table No. 2 N-(3,4-dihydro-1H-oxazino[1,4][4,3-a]benzimidazol-7-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

Compound 15 was prepared, according to a method similar to that described in Example 6, by reaction between ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate, obtained in step 2.1, and 7-aminooxazino[1,4][4,3-a]benzimidazole (Mullock, E. B., J. Chem. Soc. Section C, 1970, (6), 829-833).

Mp=216-217° C.

¹H NMR (DMSO D₆), δ (ppm): 4.15 (m, 4H); 4.91 (s, 2H); 5.85 (s, 2H); 6.82-7.61 (m, 10H); 8 (s, 1H); 10.39 (s, 1H).

EXAMPLE 29 Compound No. 133 of Table No. 2 N-[2,3-dihydro-3-(tert-butoxycarbonyl)imidazo[1,2-a]-benzimidazol-6-yl]-1-benzyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

Compound 133 is prepared, according to a process described in Example 11, from 6-amino-2,3-dihydro-1-tert-butoxycarbonylimidazo[1,2-a]benzimidazole (VII-d) and ethyl 1-benzyl-5-trifluoromethylpyrrolo[3,2-b]pyridine-2-carboxylate (23.4).

Mp=169-174° C.

¹H NMR (DMSO D₆), δ (ppm): 1.51 (s, 9H); 4.27 (m, 4H); 5.94 (s, 2H); 7.09-7.31 (m, 6H); 7.42 (dxd, 1H); 7.58 (s, 1H); 7.71 (d, 1H); 7.84 (s, 1H); 8.29 (d, 1H); 10.52 (s, 1H).

EXAMPLE 30 Compound No. 137 of Table No. 2 N-(2,3-dihydroimidazo[1,2-a]benzimidazol-6-yl)-1-benzyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide

A solution of 0.18 g (0.31 mmol) of compound 133 (Example 29) in 10 ml of 2M hydrochloric acid in diethyl ether is stirred at 20° C. for 16 hours. After this period of time, the expected product 137 is isolated by filtering off a yellow precipitate which is dried under reduced pressure.

¹H NMR (DMSO D₆), δ (ppm): 4.3 (m, 4H); 5.98 (s, 2H); 7.11 (m, 1H); 7.25 (m, 3H); 7.41 (d, 1H); 7.59 (dxd, 1H); 7.68 (s, 1H); 7.78 (d, 1H); 7.89 (s, 1H); 8.35 (d, 1H); 9.39 (s, 1H); 10.82 (s, 1H); 13.35 (s, 1H).

The following tables 2, 3 and 4 illustrate the chemical structures and the physical properties of some examples of compounds according to the invention.

In these tables:

-   -   the column “G1” represents an atom or group of atoms reading         from left to right;     -   the column “MP (° C.) or [MH]⁺” gives the melting points of the         products in degrees Celsius (° C.) or else the peak obtained by         mass spectrometry, after chemical ionization;     -   in the column “Salt/base”, “-” represents a compound in free         base form, whereas “HCl” represents a compound in hydrochloride         form and the ratio in brackets is the (acid:base) ratio;     -   “CH₃” corresponds to a methyl group, “CF₃” corresponds to a         trifluoromethyl group, “Et” corresponds to an ethyl group,         “t-Bu” corresponds to a tert-butyl group, “i-Pr” corresponds to         an isopropyl group, and “benzyl” corresponds to a phenylmethyl         group.

TABLE 2

Salt/ Mp(° C.) or No. X₁,X₂,X₃,X₄ R′ G₁ Base [MH]⁺ 1. CH, C—F, CH, CH (pyridin-4-yl)methyl (CH₂)₂ — 292-293 2. CH, C—F, CH, CH 3-fluorobenzyl (CH₂)₂ — 286-287 3. CH, CH, CH, N benzyl (CH₂)₂ — 233-235 4. CH, C—CF₃, CH, N benzyl (CH₂)₂ — 241-243 5. CH, C—F, CH, CH (pyridin-4-yl)methyl CH₂ — 266-267 6. CH, C—F, CH, CH 3-fluorobenzyl CH₂ — 256-257 7. CH, CH, CH, N benzyl CH₂ — 251-252 8. CH, C—CF₃, CH, N benzyl CH₂ — 268-270 9. CH, C—F, CH, CH 2-(pyridin-3-yl)ethyl CH₂ — 251-252 10. CH, C—F, CH, CH H CH₂ — 350-352 11. CH, C—F, CH, CH 4,5-dimethylpyridin-2-yl CH₂ — 254-255 12. CH, C—F, CH, CH 3-fluorobenzyl NH — [MH]⁺ = 444 13. CH, C—F, CH, CH Methyl CH₂ — 269-270 14. CH, C—CF₃, CH, N H CH₂ — 380-385 15. CH, C—F, CH, CH 3-fluorobenzyl CH₂O — 218-217 16. CH, C—F, CH. CH (thiazol-2-yl)methyl CH₂ — 248-249 17. CH, C—F, CH, CH 3-fluorobenzyl CHOH — 260-263 18. CH, C—F, CH, CH (3-methylpyridin-2-yl)methyl CH₂ — 247-248 19. CH, C—F, CH, CH 3-fluorobenzyl S — 246-247 20. CH, C—F, CH, CH (pyridin-4-yl)methyl CH₂O — 283-284 21. CH, C—F, CH, CH (5-methylpyridin-2-yl)methyl CH₂ — 257-280 22. CH, C—F, CH, CH (6-methylpyridin-2-yl)methyl CH₂ — 277-279 23. CH, C—F, CH, CH (pyrimidin-4-yl)methyl CH₂ — 236-241 24. CH, C—CF₃, CH, N benzyl CH₂O — 236-237 25. CH, C—F, CH, CH 3-fluorobenzyl CH₂NH HCl 276-284 1:1 26. CH, C—F, CH, CH 3-fluorobenzyl NCH₃ — 281-282 27. CH, C-tBu, CH, CH (pyridin-4-yl)methyl CH₂ — 273-274 28. C—OCH₃, CH, CH, (pyridin-4-yl)methyl CH₂ — 304-305 C—CH₃ 29. CH, CH, C— (pyridin-4-yl)methyl CH₂ — 282-283 N(CH₃)₂, CH 30. CH, CH, C—CF₃, CH (pyridin-4-yl)methyl CH₂ — 284-285 31. C—Br, CH, CH, CH (pyridin-4-yl)methyl CH₂ — 304-305 32. CH, CH, C-tBu, CH (pyridin-4-yl)methyl CH₂ — 241-242 33. CH, CCl, CH, CH (pyridin-4-yl)methyl CH₂ — [MH]⁺ 442 34. C—CH₃, CH, C—CH₃, (pyridin-4-yl)methyl CH₂ — 291-292 CH 35. CH, CH, CH, CH (pyridin-4-yl)methyl CH₂ — 290-291 36. C—CH₃, CH, C—H, (pyridin-4-yl)methyl CH₂ — 310-311 CH 37. CH, CH, C—SCH₃, (pyridin-4-yl)methyl CH₂ — 263-264 CH 38. CH, CH, C-iPr, CH (pyridin-4-yl)methyl CH₂ — 262-263 39. CH, CH, C-Et, CH (pyridin-4-yl)methyl CH₂ — 255-256 40. CH, CH, CBr, CH (pyridin-4-yl)methyl CH₂ — 298-299 41. CH, C—NO₂, CH, (pyridin-4-yl)methyl CH₂ — [MH]⁺ 453 CH 42. C—CH₃, CH, CH, C— (pyridin-4-yl)methyl CH₂ — 308-309 CH₃ 43. CH, C—SO₂CH₃, (pyridin-4-yl)methyl CH₂ — [MH]⁺ 486 CH, CH 44. C—F, CH, CH, CH (pyridin-4-yl)methyl CH₂ — 275-276 CH, CH 45. CH, CH, C-OiPr, (pyridin-4-yl)methyl CH₂ — 257-258 CH 46. CH, CH, C—CH₃, (pyridin-4-yl)methyl CH₂ — 302-303 CH 47. C—CH₃, CH, C—O (pyridin-4-yl)methyl CH₂ — 311-312 CH₃, C—CH₃ 48. CH, CH, CH, C-iPr (pyridin-4-yl)methyl CH₂ — 210-211 49. CH, C—CF₃, CH, N 3-fluorobenzyl CH₂ — 253-254 50. CH, C—CF₃, CH, N (quinolin-2-yl)methyl CH₂ — 300-301 51. CH, C—CF₃, CH, N (quinoxalin-2-yl)methyl CH₂ — [MH]⁺ 528 52. CH, C—CF₃, CH, N (5-trifluoromethylfuran-2-yl) CH₂ — [MH]⁺ 534 methyl 53. CH, C—CF₃, CH, N 3-(dimethylamino)benzyl CH₂ — [MH]⁺ 519 54. CH, C—CF₃, CH, N (pyridin-3-yl)methyl CH₂ — [MH]⁺ 477 55. CH, C—CF₃, CH, N (pyridin-2-yl)methyl CH₂ — [MH]⁺ 477 56. CH, C—CF₃, CH, N (6-methylpyridin-2-yl)methyl CH₂ — [MH]⁺ 491 57. CH, C—CF₃, CH, N (2-methylpyridin-3-yl)methyl CH₂ — [MH]⁺ 491 58. CH, C—CF₃, CH, N (2-methylpyridin-4-yl)methyl CH₂ — 275-276 59. CH, C—CF₃, CH, N (6-trifluoromethylpyridin-3-yl) CH₂ — [MH]⁺ 545 methyl 60. CH, C—CF₃, CH, N (pyrazin-2-yl)methyl CH₂ — [MH]⁺ 478 61. CH, C—CF₃, CH, N (5-methylpyrazin-2-yl)methyl CH₂ — 316-317 62. CH, C—CF₃, CH, N (thiazol-2-yl)methyl CH₂ — [MH]⁺ 483 63. CH, C—CF₃, CH, N (benzothiazol-2-yl)methyl CH₂ — 307-308 64. CH, C—CF₃, CH, N [2-(morpholin-1-yl)-pyridin-3- CH₂ — [MH]⁺ 562 yl]methyl 65. CH, C—CF₃, CH, N 2- CH₂ — 276-277 (diethylaminocarbonyl)methyl 66. CH, C—F, CH, CH 3-(dimethylamino)benzyl CH₂ — 292-293 67. CH, C—F, CH, CH 2-fluorobenzyl CH₂ — 250-251 68. CH, C—F, CH, CH 4-fluorobenzyl CH₂ — 218-219 69. CH, C—F, CH, CH 4-(imidazol-1-yl)benzyl CH₂ — [MH]⁺ 491 70. CH, C—F, CH, CH benzyl CH₂ — 232-233 71. CH, C—F, CH, CH (6-trifluoromethylpyridin-3-yl) CH₂ — 251-252 methyl 72. CH, C—F, CH, CH (2-methylpyridin-3-yl)methyl CH₂ — 291-292 73. CH, C—F, CH, CH (pyridin-2-yl)ethyl CH₂ — 180-181 74. CH, C—F, CH, CH (pyridin-4-yl)ethyl CH₂ — [MH]⁺ 440 75. CH, C—F, CH, CH (pyridin-3-yl)propyl CH₂ — 208-209 76. CH, C—F, CH, CH (pyridin-4-yl)propyl CH₂ — [MH]⁺ 454 77. CH, C—F, CH, CH (pyridin-2-yl)propyl CH₂ — 170-171 78. CH, C—F, CH, CH (6-methylpyridin-2-yl)propyl CH₂ — [MH]⁺ 468 79. CH, C—F, CH, CH [2-(4-methylphenylthio)- CH₂ — [MH]⁺ 548 pyridin-3-yl]methyl 80. CH, C—F, CH, CH (quinolin-3-yl)methyl CH₂ — [MH]⁺ 476 81. CH, C—F, CH, CH 3-fluorobenzyl CH₂N(CH₃) — [MH]⁺ 472 82. CH, C—F, CH, CH 2-[5-methylpyridin-2- CH₂ — 209-210 yloxy]ethyl 83. CH, C—F, CH, CH 2-[(5-trifluoromethyl)-pyridin- CH₂ — [MH]⁺ 524 2-yloxy]ethyl 84. CH, C—F, CH, CH 2-(benzyloxy)ethyl CH₂ — 186-187 85. CH, CH, CH, N 3-methoxybenzyl CH₂ — 407-408 86. CH, CH, CH, N 2-fiuorobenzyl CH₂ — [MH]⁺ 426 87. CH, CH, CH, N 4-fluorobenzyl CH₂ — 350-351 88. CH, CH, CH, N 3-chlorobenzyl CH₂ — [MH]⁺ 442 89. CH, CH, CH, N 3-methylbenzyl CH₂ — 211-212 90. CH, CH, CH, N (naphth-1-yl)methyl CH₂ — [MH]⁺ 458 91. CH, CH, CH, N 2-(3-trifluoromethyl- CH₂ — 281-282 phenyl)ethyl 92. CH, CH, CH, N 2-(2-trifluoromethyl- CH₂ — 230-231 phenyl)ethyl 93. CH, CH, CH, N 2-(3-fluorophenyl)ethyl CH₂ — [MH]⁺ 440 94. CH, CH, CH, N 2-(4-fluorophenyl)ethyl CH₂ — 233-234 95. CH, CH, CH, N 3-phenylpropyl CH₂ — [MH]⁺ 436 96. CH, CH, CH, N (pyridin-3-yl)methyl CH₂ — [MH]⁺ 409 97. CH, CH, CH, N (4-methyl-2-phenylpyrimidin- CH₂ — [MH]⁺ 500 5-yl)methyl 98. CH, CH, CH, N (pyridin-2-yl)methyl CH₂ — 265-266 99. CH, CH, CH, N (6-methylpyridin-2-yl)methyl CH₂ — 262-263 100. CH, CH, CH, N (2-methylpyridin-4-yl)methyl CH₂ — 263-264 101. CH, CH, CH, N (2-methylpyridin-3-yl)methyl CH₂ — [MH]⁺ 423 102. CH, CH, CH, N (6-trifluoromethylpyridin-3-yl) CH₂ — [MH]⁺ 477 methyl 103 CH, CH, CH, N [6-(pyrrolidin-1-yl)pyridin-3- CH₂ — [MH]⁺ 478 104. CH, CH, CH, N [6-(N-diethylamino)pyridin-3- CH₂ — 227-228 yl)methyl 105. CH, CH, CH, N [2-(pyrrolidin-1-yl)pyridin-3- CH₂ — [MH]⁺ 478 yl)methyl 106. CH, CH, CH, N [6-(morpholin-1-yl)pyridin-3- CH₂ — 252-253 yl)methyl 107. CH, CH, CH, N 2-(pyridin-2-yl)ethyl CH₂ — [MH]⁺ 423 108. CH, CH, CH, N 2-(pyridin-3-yl)ethyl CH₂ — 408-409 109. CH, CH, CH, N 2-(pyridin-4-yl)ethyl CH₂ — [MH]⁺ 423 110. CH, CH, CH, N 3-(pyridin-4-yl)propyl CH₂ — [MH]⁺ 437 111. CH, CH, CH, N 3-(pyridin-3-yl)propyl CH₂ — 217-218 112. CH, CH, CH, N 3-(6-methylpyridin-2-yl)propyl CH₂ — 182-183 113. CH, CH, CH, N (quinolin-2-yl)methyl CH₂ — 254-255 114. CH, CH, CH, N (quinolin-3-yl)methyl CH₂ — 275-276 115. CH, CH, CH, N (quinolin-4-yl)methyl CH₂ — [MH]⁺ 459 116. CH, CH, CH, N (3,5-dimethyl-4- CH₂ — 275-276 methoxypyridin-2-yl)methyl 117. CH, CH, CH, N (quinolin-6-yl)methyl CH₂ — 286-287 118. CH, CH, CH, N 3-(N-dimethylamino)benzyl CH₂ — 155-156 119. CH, CH, CH, N (quinoxalin-2-yl)methyl CH₂ — 287-288 120. CH, CH, CH, N [2-(4- CH₂ — [MH]⁺ 531 methylphenylthio)pyridin-3- yl]methyl 121. CH, CH, CH, N (pyrazin-2-yl)methyl CH₂ — [MH]⁺ 410 122. CH, CH, CH, N (5-methylpyrazin-2-yl)methyl CH₂ — [MH]⁺ 424 123. CH, CH, CH, N (benzothiazol-2-yl)methyl CH₂ — [MH]⁺ 465 124. CH, CH, CH, N (thiazol-2-yl)methyl CH₂ — [MH]⁺ 415 125. CH, CH, CH, N 2- CH₂ — 271-272 (diethylaminocarbonyl)methyl 126. CH, CH, CH, N (5-trifluoromethylfuran-2-yl) CH₂ — [MH]⁺ 466 methyl 127. CH, C—F, CH, N benzyl CH₂O — 231-232 128. CH, C—F, CH, N benzyl CH₂ — 259-260 129. N, C—CF₃, CH, CH benzyl CH₂ — 251-252 130. CH, C—F, CH, N (pyridin-4-yl)methyl CH₂ — 283-285 131. N, C—CF₃, CH, CH (pyridin-4-yl)methyl CH₂ — 270-271 132. CH, C—F, CH, CH 3-fluorobenzyl N(CH₃)CH₂ HCl 343-349 (1:1) 133. N, C—CF₃, CH, CH benzyl NC(O)OtBu — 169-174 134. CH, C—F, CH, N benzyl NC(O)OtBu — 160-164 135. CH, C—F, CH, N (pyridin-4-yl)methyl NC(O)OtBu — 303-308 136. CH, C—F, CH, CH 3-fluorobenzyl NC(O)OtBu — [MH]⁺ 544 137. N, C—CF₃, CH, CH benzyl NH HCl [MH]⁺ 477 (2:1) 138. CH, C—F, CH, N benzyl NH HCl [MH]⁺ 427 (1:1) 139. CH, C—F, CH, N (pyridin-4-yl)methyl NH — [MH]⁺ 428 140. CH, C—CF₃, CH, N benzyl N(Me) HCl 337-339 (1:1) 141. CH, C—F, CH, N benzyl N(Me) HCl 330-333 (1:1) 142. CH, C—F, CH, N (pyridin-4-yl)methyl N(Me) HCl 318-320 (3:2) 143. CH, C—F, CH, CH 3-fluorobenzyl N(Me)(CH₂)₂ HCl 325-331 1:1 144. CH, C—CF₃, CH, N benzyl NH HCl [MH]⁺ 477 (1:1) 145. CH, C—CF₃, CH, N (pyridin-4-yl)methyl CH₂ — 278-279 146. CH, C—CF₃, CH, N (pyridin-4-yl)methyl CH₂O — 299-300 147. CH, C—CF₃, CH, N benzyl NC(O)OtBu — [MH]⁺ 577

The NMR data of some examples from the table are indicated hereinafter, by way of examples.

NMR for Compound No. 9: ¹H NMR (DMSO D₆), δ (ppm): 2.68 (m, 2H); 2.98 (t, 2H); 3.04 (t, 2H); 4.11 (t, 2H); 4.82 (t, 2H); 7.1 (dxt, 1H); 7.2 (m, 1H); 7.3 (s, 1H); 7.49 (m, 5H); 8 (s, 1H); 8.3 (s, 1H); 8.32 (d, 1H); 10.11 (s, 1H).

NMR for Compound No. 10: ¹H NMR (DMSO D₆), δ (ppm): 2.61 (m, 2H); 2.92 (t, 2H); 4.08 (t, 2H); 7.05 (dxt, 1H); 7.41 (m, 5H); 8.03 (s, 1H); 10.19 (s, 1H); 11.8 (s, 1H).

NMR for Compound No. 11: ¹H NMR (DMSO D₆), δ (ppm): 2.32 (s, 3H); 2.4 (s, 3H); 2.61 (m, 2H); 2.8 (t, 2H); 4.06 (t, 2H); 7.11 (m, 3H); 7.41 (m, 5H); 7.89 (s, 1H); 10.4 (s, 1H);

NMR for Compound No. 12: ¹H NMR (DMSO D₆), δ (ppm): 4.27 (m, 4H); 5.88 (s, 2H); 6.89 (m, 2H); 7.02 (txd, 1H); 7.14 (txd, 1H); 7.31 (m, 2H); 7.42 (s, 1H); 7.59 (m, 3H); 7.99 (s, 1H); 9.39 (s, 1H); 10.61 (s, 1H);

NMR for Compound No. 13: ¹H NMR (DMSO D₆), δ (ppm): 2.61 (m, 2H); 2.91 (t, 2H); 4.03 (s, 3H); 4.1 (t, 2H); 7.11 (dxt, 1H); 7.25 (s, 1H); 7.48 (m, 4H); 8.1 (s, 1H); 10.25 (s, 1H);

NMR for Compound No. 14: ¹H NMR (DMSO D₆), δ (ppm): 2.61 (m, 2H); 2.90 (t, 2H); 4.08 (t, 2H); 7.4 (m, 3H); 8.01 (s, 1H); 8.6 (d, 2H); 10.3 (s, 1H); 12.78 (s, 1H);

NMR for Compound No. 17: ¹H NMR (DMSO D₆), δ (ppm): 2.39 (m, 1H); 2.89 (m, 1H); 4.02 (m, 1H); 4.18 (m, 1H); 5.07 (m, 1H); 5.85 (s, 2H); 6.8 (m, 2H); 6.97-7.32 (m, 3H); 7.34-7.6 (m, 5H); 8.02 (s, 1H).

NMR for Compound No. 18: ¹H NMR (DMSO D₆), δ (ppm): 2.4 (s, 3H); 2.59 (m, 2H); 2.9 (t, 2H); 4.05 (t, 2H); 5.95 (s, 2H); 6.92-7.11 (m, 2H); 7.27-7.58 (m, 6H); 7.89 (d, 1H); 8.02 (d, 1H); 10.09 (s, 1H).

NMR for Compound No. 49: ¹H NMR (DMSO D₆), δ (ppm): 2.66 (m, 2H); 2.95 (dxd, 2H); 4.11 (dxd, 2H); 6 (s, 2H); 6.93 (m, 2H); 7.05 (dxt, 1H); 7.3-7.5 (m, 3H); 7.59 (s, 1H); 7.95 (d, 1H); 8.71 (d, 1H); 8.81 (d, 1H); 10.55 (s, 1H).

NMR for Compound No. 136: ¹H NMR (DMSO D₆), δ (ppm): 1.51 (s, 9H); 4.27 (m, 4H); 5.92 (s, 2H); 7.09-7.3 (m, 6H); 7.41 (dxd, 1H); 7.61 (s, 1H); 7.85 (s, 1H); 8.66 (s, 1H); 8.79 (s, 1H); 10.45 (s, 1H).

NMR for Compound No. 138: ¹H NMR (DMSO D₆), δ (ppm): 4.3 (m, 4H); 5.92 (s, 2H); 7.1 (m, 2H); 7.21 (m, 3H); 7.39 (d, 1H); 7.41 (s, 1H); 7.58 (d, 1H); 7.99 (s, 1H); 8.17 (dxd, 1H); 8.49 (s, 1H); 9.3 (s, 1H); 10.62 (s, 1H).

NMR for Compound No. 139: ¹H NMR (DMSO D₆), δ (ppm): 4.03 (m, 4H); 5.92 (s, 2H); 6.92 (s, 1H); 7.05 (m, 3H); 7.23 (d, 1H); 7.46 (s, 1H); 7.56 (s, 1H); 8.19 (dxd, 1H); 8.41 (d, 3H); 10.32 (s, 1H).

NMR for Compound No. 143: ¹H NMR (CDCL₃), δ (ppm): 2.25 (m, 4H); 3.41 (s, 3H); 3.49 (m, 2H); 4.24 (m, 2H); 6.15 (s, 2H); 7.01-7.37 (m, 6H); 7.41-7.65 (m, 3H); 7.79 (m, 2H); 8.25 (s, 1H).

NMR for Compound No. 144: ¹H NMR (DMSO D₆), δ (ppm): 4.29 (m, 4H); 5.98 (s, 2H); 7.11 (m, 2H); 7.25 (m, 3H); 7.4 (d, 1H); 7.55 (d, 1H); 7.57 (s, 1H); 7.99 (s, 1H); 8.71 (s, 1H); 8.8 (s, 1H); 9.26 (s, 1H); 10.74 (s, 1H).

NMR for Compound No. 145: ¹H NMR (DMSO D₆), δ (ppm): 2.61 (m, 2H); 2.92 (t, 2H); 4.09 (t, 2H); 5.98 (s, 2H); 7.01 (d, 2H); 7.41 (m, 2H); 7.62 (s, 1H); 7.9 (s, 1H); 8.39 (d, 2H); 8.71 (d, 2H); 10.55 (s, 1H).

NMR for Compound No. 146: ¹H NMR (DMSO D₆), δ (ppm): 4.19 (m, 4H); 4.95 (s, 2H); 6 (s, 2H); 7.05 (m, 2H); 7.51 (m, 2H); 7.66 (s, 1H); 7.99 (s, 1H); 8.44 (d, 2H); 8.78 (d, 2H).

TABLE 3

Salt/ No. X Y R′ Base Mp (° C.) 148. CH CH 3-fluorobenzyl — 261-262 149. CH CH (pyridin-4-yl)methyl — 277-278 150. N CH 3-fluorobenzyl — 295-298 151. CH N 3-fluorobenzyl HCl 1:1 225-230

TABLE 4

Mp (° C.) Salt/ or No. R′ G₂ G₃ Base [MH]⁺ 152. (pyridin-4-yl)methyl CH₂ CH(CH₃) HCl 1:1 285-290 153. (pyridin-4-yl)methyl CHOH CH₂ HCl 1:1 295-300 154. 3-fluorobenzyl CHOCH₃ CH₂ HCl 1:1 220-225

The NMR data of some examples from the table are indicated hereinafter, by way of examples:

NMR for Compound No. 152: ¹H NMR (DMSO D₆), δ (ppm): 1.59 (d, 3H); 2.38 (m, 1H); 2.94 (m, 1H); 3.33 (m, 2H); 4.87 (m, 1H); 6.5 (s, 2H); 7.2 (dxt, 1H); 7.36 (d, 2H); 7.5-7.7 (m, 3H); 7.84 (m, 2H); 8.35 (s, 1H); 8.65 (d, 2H).

NMR for Compound No. 153: ¹H NMR (DMSO D₆), δ (ppm): 3.11 (d, 1H); 3.62 (dxd, 1H); 4.2 (dxd, 1H); 4.49 (dxd, 1H); 5.1 (m, 1H); 6.09 (s, 2H); 7.19 (dxt, 1H); 7.43 (d, 2H); 7.5-7.7 (m, 3H); 7.81 (d, 2H); 8.32 (s, 1H); 8.7 (d, 2H); 10.7 (s, 1H).

The compounds according to the invention were the subject of in vitro and in vivo pharmacological assays which demonstrated their advantage as substances with therapeutic activities. These compounds have an antagonist or agonist activity with respect to TRPV1 (or VR1) receptors.

Test for Inhibition of the Current Induced by Capsaicin on Rat DRGs

Primary Culture of Rat Dorsal Root Ganglion (DRG) Cells:

The neurons of the DRG naturally express the TRPV1 receptor.

Newborn rat DRG primary cultures are prepared from 1-day-old rat pups. Briefly, after dissection, the ganglia are trypsinized and the cells are mechanically dissociated by controlled trituration. The cells are resuspended in an Eagle's basal culture medium containing 10% of fetal calf serum, 25 mM KCl, 2 mM glutamine, 100 μg/ml gentamicin and 50 ng/ml of NGF, and then deposited onto laminin-coated glass cover slips (0.25×10⁶ cells per cover slip) which are then placed in 12-well Corning dishes. The cells are incubated at 37° C. in a humidified atmosphere containing 5% CO₂ and 95% air. Cytosine β-D-arabinoside (1 μM) is added 48 h after placing in culture, in order to prevent the development of non-neuronal cells. The cover slips are transferred into the experimental chambers for the patch-clamp studies after 7-10 days of culture.

Electrophysiology:

The measuring chambers (volume 800 μl) containing the cell preparation are placed on the platform of an inverted microscope (Olympus IMT2) equipped with Hoffman optics (Modulation Contrast, New York), and observed at the magnification of ×400. The chambers are continually perfused by gravity (2.5 ml/min) by means of a solution distributing device with 8 inlets, and the sole outlet of which, consisting of a polyethylene tube (500 μm aperture), is placed less than 3 mm from the cell studied. The “whole cell” configuration of the patch-clamp technique was used. The borosilicate glass pipettes (resistance 5-10 MOhms) are moved close to the cell by means of a 3D piezoelectric micromanipulator (Burleigh, PC1000). The overall currents (membrane potential fixed at −60 mV) are recorded with an Axopatch 1D amplifier (Axon Instruments, Foster City, Calif.), connected to a PC controlled by Pclamp8 software (Axon Instrument). The current traces are recorded on paper and simultaneously digitized (sampling frequency 15 to 25 Hz) and acquired on the hard drive of the PC.

The application of a 300 nM solution of capsaicin causes, on the DRG cells (voltage fixed at −70 mV), an inward cationic current. In order to minimize desensitization of the receptors, a minimum period of one minute is observed between two applications of capsaicin. After a controlled period (stabilization of the capsaicin response alone), the compounds of the invention to be tested are applied alone at a given concentration (concentration of 10 nM or of 1 nM) for a period of 4 to 5 minutes, during which several capsaicin+compound tests are carried out (obtaining of maximum inhibition). The results are expressed as % inhibition of the control capsaicin response.

In the case of the VR1 antagonist compounds, the percentages of inhibition of the capsaicin response (1 microM) are between 20% and 100% for the most active compounds of the invention tested at concentrations of 0.1 to 10 nM. These are therefore effective antagonists of TRPV1-type receptors. Table 5 gives some examples of the % inhibition obtained with the compounds of the invention.

TABLE 5 Compound No. % inhibition in DRG patch 1 37% (10 nM) 5 53% (10 nM)

The actual agonist effect of the compounds can be evaluated by measuring the current induced at various concentrations of compound on the rat DRG, in the presence or absence of capsazepine.

Mouse Corneal Irritation Test

The irritant nature of capsaicin can be readily assessed at the level of the cornea since this organ is one of the most innervated by C fibers. In this context, according to the preliminary experiments, the application of a very small amount of capsaicin (2 μl at a concentration of 160 μM) to the surface of the cornea of an animal results in a certain number of stereotyped behaviors associated with the irritation and that can be readily listed. Among these are: blinking of the eye, rubbing of the eye instilled with the ipsilateral forelimb, rubbing of the face with both forelimbs, scratching of the ipsilateral face with the hind limb. The duration of these behaviors does not exceed the 2 minutes of observation and the animal then returns to its normal activity. Its appearance is, moreover, also normal. The mouse is not hidden away in a corner with its coat bristling and does not develop any observable sign of sufferance. It can be concluded from this that the duration of action of capsaicin at these doses is less than 2 minutes.

Summary of the Methodology:

The principle of the series of experiments is to determine whether the compounds of the invention can influence the behavioral response induced by a given amount of capsaicin. The capsaicin is initially diluted to 25 mM in DMSO and diluted, for its final use, in physiological saline with 10% Tween 80. It appears, based on control studies, that, under these conditions, the solvent has no effect.

In practice, the product to be tested, prepared at 25 mM in DMSO and diluted for its final use in physiological saline with 10% Tween 80, at the highest concentration of 500 μM, is administered by local application to the surface of the cornea in a volume of 2 μl, 10 minutes before the application of the capsaicin. The animal receives the ocular instillation of 2 μl of a solution of capsaicin at 160 μm prepared as indicated above. Over the course of a period of observation of 2 minutes following the instillation, the number of times the instilled eye is rubbed by the ipsilateral forelimb is counted for each animal.

For a given group, the percentage protection is calculated as follows: P=100−((average number of scratches of the group treated with the compound/average number of scratches of the group treated with the solvent)×100).

This percentage protection is averaged for each group of animals (n=number of animals tested with the compound of the invention).

The protection percentages evaluated, in this model, for the most active compounds of the invention, used at the concentration of 500 μM, are between 20% and 100% (see example in Table 6):

TABLE 6 Compound No. % P 500 μM 8 71% 15 56% 26 46%

The results of these assays show that the most active compounds of the invention block, in vivo, the effects induced by the stimulation of TRPV1 receptors.

The compounds of the invention can therefore be used for the preparation of medicaments, in particular for the preparation of a medicament for preventing or treating pathologies in which TRPV1-type receptors are involved.

The compounds of the invention can be used for preventing or treating pathologies in which TRPV1-type receptors are involved.

Thus, a subject of the invention is medicaments which comprise at least one compound of formula (I), or a pharmaceutically acceptable salt, or else a hydrate or a solvate of said compound.

These medicaments can be used in therapeutics, in particular in the prevention and/or treatment of pain and inflammation, chronic pain, neuropathic pain (trauma-related, diabetic, metabolic, infection-related or toxic pain, or pain induced by an anticancer or iatrogenic treatment), (osteo)arthritic pain, rheumatic pain, fibromyalgia, back pain, cancer-related pain, facial neuralgia, headaches, migraine, dental pain, burns, sunburn, animal bites or insect bites, post-herpetic neuralgia, muscle pain, trapped nerves (central and/or peripheral), spinal column and/or brain trauma, ischaemia (of the spinal column and/or of the brain), neurodegeneration, hemorrhagic strokes (of the spinal column and/or of the brain) and post-stroke pain.

The compounds of the invention can also be used for preventing and/or treating metabolic disorders such as diabetes.

The compounds of the invention can also be used for preventing and/or treating urological disorders such as bladder hyperactivity, bladder hyperreflexia, bladder instability, incontinence, urgent urination, urinary incontinence, cystitis, nephritic colic, pelvic hyper-sensitivity and pelvic pain.

The compounds of the invention can be used for preventing and/or treating gynecological disorders such as vulvodynia and pain associated with salpingitis or with dysmenorrhea.

These products can also be used for preventing and/or treating gastrointestinal disorders such as gastro-oesophageal reflex disorder, stomach ulcers, duodenal ulcers, functional dyspepsia, colitis, IBS, Crohn's disease, pancreatitis, oesophagitis and biliary colic. Similarly, the products of the present invention can be used in the prevention and/or treatment of respiratory disorders such as asthma, coughing, chronic obstructive pulmonary disease (COPD), bronchoconstriction and inflammatory disorders.

These products can also be used for preventing and/or treating psoriasis, pruritis, dermal, ocular or mucosal irritations, herpes and shingles.

The compounds of the invention can also be used for treating depression.

The compounds of the invention can also be used for treating central nervous system diseases such as multiple sclerosis.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or a solvate of said compound, and also at least one pharmaceutically acceptable excipient.

Said excipients are selected according to the pharmaceutical form and the desired method of administration, from the usual excipients known to those skilled in the art.

The pharmaceutical compositions of the present invention can be administered orally, sublingually, subcutaneously, intramuscularly, intravenously, topically, locally, intratracheally, intranasally, transdermally or rectally. These compositions can be administered in unit form, as a mixture with conventional pharmaceutical excipients. They are intended to be administered to animals and to human beings for the prophylaxis or treatment of the disorders or diseases mentioned above.

The appropriate unit administration forms include oral forms such as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodium croscaramellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

Said unit forms are dosed so as to allow a daily administration of from 0.001 to 30 mg of active ingredient per kg of body weight, according to the galenical form.

There may be specific cases where higher or lower dosages are appropriate; such dosages do not depart from the scope of the invention. According to the usual practice, the dosage that is appropriate for each patient is determined by the physician according to the method of administration and the weight and the response of said patient.

The compounds of the invention can also be used for the preparation of medicaments, in particular for the preparation of a medicament for use in preventing or treating pathologies in which TRPV1-type receptors are involved, as mentioned above.

According to another of its aspects, the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or a solvate thereof. 

1. A compound of the formula (I):

in which: A is, with the C—N bond of the benzimidazole unit with which it is fused, a 4- to 7-membered monocyclic heterocycle or monocyclic heteroaryl, containing from one to three heteroatoms selected from O, S and N, including the nitrogen atom of the benzimidazole unit; P is an 8-, 9-, 10- or 11-membered bicyclic heterocycle or bicyclic heteroaryl, containing from 1 to 6 heteroatoms selected from N, O and S; P being linked to the —C(Y)— group by a carbon atom; with the proviso that, when A is a 7-membered saturated heterocycle, P is other than the 2,3-dihydro-1,4-benzodioxane group, the 1-benzopyran-2-one group and the isoindole group; R1 is substituted on P one to four times and each R1 may be identical or different, R1 selected from a hydrogen atom, a halogen atom, and an oxo, thio, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, aryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl, heteroaryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, aryl-C₁-C₃-alkylenethio-C₁-C₆-alkyl, heteroaryl-C₁-C₃-alkylenethio-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy, C₁-C₆-fluoroalkoxy, cyano, C(O)NR₄R₅, nitro, NR₄R₅, C₁-C₆-thioalkyl, C₃-C₇-cycloalkylthio, C₃-C₇-cycloalkyl-C₁-C₃-alkylenethio, —S(O)—C₁-C₆-alkyl, —S(O)—C₃-C₇-cycloalkyl, —S(O)—C₁-C₃-alkylene-C₃-C₇-cycloalkyl, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, SO₂NR₄R₅, SF₅, NR₆C(O)R₇, NR₆SO₂R₈, R₄R₅NC(O)—C₁-C₃-alkylene, aryl, heteroaryl, aryl-C₁-C₅-alkylene, heteroaryl-C₁-C₅-alkylene, aryloxy, arylthio, heteroaryloxy or heteroarylthio group; said heteroaryl or aryl groups of R1 being optionally substituted with one or more substituents R₉, which may be identical to or different from one another; with the proviso that, when R1 is attached to a nitrogen atom of P, then R1 is not a halogen atom, an oxo, thio, cyano, nitro, SF₅, NR₄R₅, C₁-C₆-thioalkyl, thioaryl, thioheteroaryl, C₁-C₆-alkoxy, aryloxy, heteroaryloxy, —NR₆COR₇ or NR₆SO₂R₈ group; Y is an oxygen or sulphur atom; R2 is a hydrogen atom, a halogen atom, or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl or C₁-C₆-alkoxy group; R3 is substituted on a carbon atom of A, each R3 may be substituted 1 to 3 times on a carbon atom of A, each R3 substituted on a carbon atom of A may be identical or different, said R3 substituted on a carbon atom of A selected from hydrogen, halogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, hydroxyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy and C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy group; or R3 is substituted on a nitrogen atom of A, each R3 may be substituted once or twice on a nitrogen atom of A and may be identical or different, said R3 substituted on a nitrogen atom of A selected from hydrogen, halogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C(O)—, C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-C(O)—, C₁-C₆-fluoroalkyl-C(O)—, aryl-S(O)₂—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoro-alkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, C₁-C₆-alkyl-O—C(O)—, aryl-C₁-C₃-alkyl-O—C(O)—, C₃-C₇-cycloalkyl-O—C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-O—C(O)—, C₁-C₆-fluoroalkyl-O—C(O)—, aryl-O—C(O)— or heteroaryl-O—C(O)— group; R₄ and R₅ are, independently of one another, a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₅-alkylene or aryl group; or R₄ and R₅ form, together with the nitrogen atom which carries them, an azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, the NR₄R₅ group being optionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene, aryl, heteroaryl, aryl-S(O)₂—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, aryl-C(O)—, C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-C(O)—, C₁-C₆-fluoroalkyl-C(O)—, hydroxyl, C₁-C₆-alkyloxy, C₁-C₆-fluoroalkyl, aryloxy-C₁-C₆-alkylene, aryloxy, heteroaryloxy-C₁-C₆-alkylene or heteroaryloxy group; R₆ and R₇ are, independently of one another, a hydrogen atom, or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene or aryl group; or R₆ and R₇ together form a 4- to 7-membered lactam comprising the nitrogen atom and the C(O) group which carry them; R₈ is a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, aryl-C₁-C₆-alkylene or aryl group; or R₆ and R₈ together form a 4- to 7-membered sultam comprising the nitrogen atom and the S(O)₂ group which carry them; R₉ is a halogen atom, or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkoxy, nitro, cyano, NR₄R₅, R₄R₅N—C₁-C₃-alkylene, aryl, heteroaryl, aryloxy, arylthio, heteroaryloxy or heteroarylthio group, said heteroaryl or aryl groups being optionally substituted with one or more substituents selected from a halogen atom, and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkoxy, nitro, cyano, NR₄R₅ or R₄R₅N—C₁-C₃-alkylene group; the sulphur atom(s) of the heterocycle A may be in oxidized form (S(O) or S(O)₂); the nitrogen atom(s) may be in oxidized form (N-oxide); or an addition salt thereof; and with the proviso that 2-(2-chlorophenyl)-1,3-dioxo-N-(7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazol-3-yl)isoindoline-5-carboxamide is excluded.
 2. The compound according to claim 1, which is of formula (II):

in which: X is a carbon atom or a nitrogen atom; said X being identical to or different from one another and the number of X═N not being greater than 2; R2, R3, Y and A being as defined in formula (I) according to claim 1; and each R1 maybe the same or different and is defined as in Formula I according to claim 1; or an addition salt thereof.
 3. The compound according to claim 2, which is of formula (III):

in which: R_(1a) is bonded to the ring containing X atoms one or more times, each R_(1a) may be identical or different, each R_(1a) is selected from hydrogen, a halogen a C₁-C₆-alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-thioalkyl, C₁-C₆-alkyl-S(O)₂—, NR₄R₅ and nitro group; R_(1b) is a hydrogen atom, or a C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, aryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl, R₄R₅NC(O)—C₁-C₃-alkylene, aryl, heteroaryl, aryl-C₁-C₆-alkylene or heteroaryl-C₁-C₆-alkylene group; said heteroaryl or aryl groups of R_(1b) being optionally substituted with one or more substituents R₉, which may be identical to or different from one another; R₉ is a halogen atom or a C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkyl, aryl, heteroaryl, NR₄R₅ or arylthio group, said heteroaryl or aryl groups being optionally substituted with one or more substituents selected from a halogen atom, and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkoxy, nitro, cyano or R₄R₅N—C₁-C₃-alkylene group; R2, R3, R₄, R₅, A, X and Y are as defined in formula (II) according to claim 2; or an addition salt thereof.
 4. The compound according to claim 1, which is of formula (IV):

in which W is a tricyclic heterocycle or a tricyclic heteroaryl selected from:

and wherein: R1, R2, R3, P and Y being as defined in formula (I) according to claim 1; or an addition salt thereof.
 5. The compound according to claim 1, which is of formula (V):

in which: R1, R2, R3, A and P are as defined in formula (I) according to claim 1; or an addition salt thereof.
 6. The compound according to claim 1, which is of formula (V):

in which: R2 is a hydrogen atom, or a C₁-C₆-alkyl or C₁-C₆-alkoxy group; R3 is substituted on a carbon atom of A one to three times, each R3 substituted on a carbon atom of A may be identical or different, and is selected from hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy and hydroxyl group; or R3 is substituted on a nitrogen atom of A, one to two times, each R3 substituted on a nitrogen atom of A may be identical or different, and is selected from hydrogen, C₁-C₆-alkyl, C₁-C₆-alkyl-O—C(O)— and aryl-C₁-C₃-alkyl-O—C(O)— group; and wherein R1, A and P are as defined in formula (I) according to claim 1; or an addition salt thereof.
 7. The compound according to claim 1, which is of formula (V):

in which: A is, with the C—N bond of the benzimidazole unit with which it is fused, a 5- to 7-membered monocyclic heterocycle or monocyclic heteroaryl containing from one to three heteroatoms selected from O, S and N, including the nitrogen atom of the benzimidazole unit; and wherein R₁, R₂, R₃, and P are as defined in formula (I) according to claim 1; or an addition salt thereof.
 8. The compound according to claim 1, which is of formula (Va):

in which A is, with the C—N bond of the benzimidazole unit with which it is fused, a 5- to 7-membered monocyclic heterocycle or monocyclic heteroaryl containing one or two heteroatoms selected from O, S and N, including the nitrogen atom of the benzimidazole unit; X is a carbon atom or a nitrogen atom; said X being identical to or different from one another and the number of X═N not being greater than 1; R_(1a) is one or more atoms or groups, which may be identical or different, selected from a hydrogen atom, a halogen atom or a C₁-C₆-alkyl group, a C₁-C₆-fluoroalkyl group, a C₁-C₆-alkoxy group, a C₁-C₆-thioalkyl group, a C₁-C₆-alkyl-S(O)₂— group, an NR₄R₅ group or a nitro group; R_(1b) is a hydrogen atom, or a C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, aryl-C₁-C₃-alkylenoxy-C₁-C₆-alkyl, R₄R₅NC(O)—C₁-C₃-alkylene, aryl, heteroaryl, aryl-C₁-C₆-alkylene or heteroaryl-C₁-C₆-alkylene group; said heteroaryl or aryl groups of R_(1b) being optionally substituted with one or more substituents R₉, which may be identical to or different from one another; R2 is a hydrogen atom; R3 is substituted on a carbon atom of X, and selected from hydrogen, C₁-C₆-alkyl, 6 C₁-C₆-alkoxy, and hydroxyl; or R3 is substituted on a nitrogen atom of X, and is selected from hydrogen, a C₁-C₆-alkyl group and a C₁-C₆-alkyl-O—C(O)— group; R₄ and R₅ are, independently of one another, a C₁-C₆-alkyl group; or R₄ and R₅ form, together with the nitrogen atom which carries them, a pyrrolidine or morpholine group; and R₉ is a halogen atom or a C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkyl, aryl, heteroaryl, NR₄R₅, or arylthio group, said aryl groups being optionally substituted with one or more C₁-C₆-alkyl groups; or an addition salt thereof.
 9. A process for preparing a compound of formula (I) according to claim 1 comprising: reacting a compound of formula (VI):

in which P, R1 and Y are as defined in formula (I) according to claim 1 and B is a C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, C₃-C₇-cycloalkyl-C₁-C₃-alkylenoxy or aryl-C₁-C₃-alkylenoxy group, with the resulting amide formed from the reaction of trimethyl-aluminum on the amine of formula VII:

in which A, R2 and R3 are as defined in formula (I) according to claim
 1. 10. A process for preparing a compound of formula (I) according to claim 1 comprising: converting a compound of formula (VI):

in which P, R1 and Y are as defined in formula (I) according to claim 1 and B is a hydroxyl group, to an acid chloride by the action of thionyl chloride at the reflux of a solvent, and reacting the compound of formula (VI) obtained therefrom, in which P, R1 and Y are as defined in formula (I) according to claim 1 and B is a chlorine atom, in the presence of a base, with the compound of formula (VII):

in which A, R2 and R3 are as defined in formula (I) according to claim 1; or subjecting to a coupling reaction a compound of formula (VI), in which P, R1 and Y are as defined in formula (I) according to claim 1 and B is a hydroxyl group, and a compound of formula (VII) in which A, R2 and R3 are as defined in formula (I) according to claim 1, in the presence of a coupling agent and a base in a solvent.
 11. A compound of formula (VIIa), (VIIb), (VIIc), (VIId), (VIIe), (VIIf), (VIIg), (VIIh), (VIIi), (VIIj), (VIIk), (VIIl), (VIIm) or (VIIn):


12. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
 13. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
 14. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
 15. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
 16. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 5 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
 17. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 6 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
 18. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 7 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
 19. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 8 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient. 